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Effect of Food and Esomeprazole on the Pharmacokinetics of Alectinib, A Highly Selective ALK Inhibitor, in Healthy Subjects
Abstract
Alectinib, an anaplastic lymphoma kinase (ALK) inhibitor, is approved for treatment of patients with ALK+ non-small-cell lung cancer who have progressed on, or are intolerant to, crizotinib. This study assessed the effect of a high-fat meal and the proton pump inhibitor, esomeprazole, on the pharmacokinetics (PK) of alectinib. This was an open-label, 2-group study in healthy subjects. In Group 1 (n = 18), subjects were randomly assigned to a 2-treatment (A: fasted conditions, B: following a high-fat meal), 2-sequence (AB or BA) crossover assessment, separated by a 10-day washout. In Group 2 (n = 24), subjects were enrolled into a 2-period, fixed-sequence crossover assessment to evaluate the effect of esomeprazole. PK parameters were evaluated for alectinib, its major similarly active metabolite, M4, and the combined exposure of alectinib and M4. Administration of alectinib following a high-fat meal substantially increased the combined exposure of alectinib and M4 to 331% (90% CI: 279, 393) and 311% (90% CI: 273, 355), for Cmax and AUC0-∞, respectively, versus fasted conditions. Co-administration of esomeprazole had no clinically relevant effect on the combined exposure of alectinib and M4,. Alectinib should be administered under fed conditions to maximize its bioavailability while no restrictions are required with antisecretory agents. This article is protected by copyright. All rights reserved
... 19 Food effects on drug bioavailability and clearance are highly variable among small-molecule kinase inhibitors. 20 Although food does not meaningfully affect crizotinib exposure, 21 food increases exposure to ceritinib, 22 and ingestion of a highfat meal increases combined exposure to alectinib and its major active metabolite M4. 23 A food effect study was conducted to assess the pharmacokinetics (PK) of brigatinib administered following a standardized high-calorie, high-fat meal, representing the setting of maximum possible perturbation of oral bioavailability in the postprandial state. Based on US FDA guidance, the recommended design for a food effect bioavailability study is a randomized, balanced, single-dose, 2-treatment (fed versus fasted), 2-period, 2-sequence crossover study, with each dose separated by an adequate washout period. ...
... Varying effects of food on the PK of other ALK inhibitors indicated for the treatment of ALK + NSCLC have been observed. [21][22][23]25 Crizotinib exposure (both C max and AUC) was 14% lower in healthy subjects following a high-fat meal. 21 The observed decrease in crizotinib exposure with food was not considered clinically meaningful; therefore, crizotinib may be taken without regard to food intake. ...
... following oral administration of a single 600-mg dose. 23 Consequently, it is recommended that alectinib be administered with food. 23 ...
Brigatinib, a next‐generation anaplastic lymphoma kinase (ALK) inhibitor, received accelerated approval in the United States for the treatment of patients with metastatic ALK+ non–small‐cell lung cancer who have progressed on or are intolerant to crizotinib. A clinical study was conducted to assess the effect of food on brigatinib pharmacokinetics (PK). Healthy subjects received a single oral dose of brigatinib 180 mg (2 × 90‐mg tablets) after a 10‐hour fast or after a high‐fat meal in a 2‐period, 2‐sequence crossover study. Plasma samples for PK characterization were collected over 168 hours postdose. Twenty‐four subjects were enrolled (mean age 44 years; 58% male), with 21 included in the PK‐evaluable population. Brigatinib peak concentration was reduced by 13% under fed (high‐fat meal) versus fasted conditions, with no effect on area under the concentration‐time curve. The median time to peak concentration of brigatinib was longer under fed conditions (5 hours) than in fasted conditions (2 hours). Treatment‐emergent adverse events were similar under fasted (48%) and fed (46%) conditions and were of mild intensity. Consumption of a high‐fat meal decreased the rate of brigatinib oral absorption but had no impact on the extent of absorption, thereby supporting brigatinib administration without regard to meals. These recommendations are reflected in the US prescribing information for brigatinib.
... Following single oral dose administration of alectinib 600 mg, plasma concentrations of alectinib increase, with a median time to maximal concentration (T max ) reached by approximately 4 to 6 hours under fed conditions, and thereafter decline with a single dose apparent half-life (t 1/2 ) of approximately 20 to 24 hours in healthy subjects and patients with cancer. [8][9][10] Dose proportionality was observed across the 300-to 900mg BID dose range. 10 In vitro studies indicate that alectinib is metabolized in the liver to its major active metabolite, M4, with cytochrome P450 3A4 (CYP3A4) being the main isoenzyme involved. ...
... Pharmacokinetic and Safety Assessments PK samples were collected for determination of total alectinib and M4 plasma concentrations at predose and 1, 2, 4, 6,8,10,12,18,24,36,48,72,96,120,144,168,192,216, and 240 hours postdose. Extended PK sampling was supported by the PBPK modeling predictions, suggesting increased exposure secondary to reduced clearance of alectinib with hepatic impairment (see Results below). ...
... Following administration of a single 300-mg alectinib dose to healthy subjects in this study, alec-tinib geometric mean PK parameters (AUC 0-Ý and C max ) were as expected and approximately half of the geometric mean values achieved in previous studies in which healthy subjects received single 600-mg alectinib doses with a similar meal type. 8,9 Following administration to hepatically impaired subjects, alectinib AUC 0-Ý GMRs were 160% and 220% for moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, respectively, compared with matched healthy subjects. Increases in exposure of ࣙ2.4-fold with hepatic impairment have been seen for other kinase inhibitors that are eliminated through hepatic metabolism. ...
Alectinib is approved and recommended as the preferred first‐line treatment for patients with anaplastic lymphoma kinase (ALK)‐positive non–small cell lung cancer. The effect of hepatic impairment on the pharmacokinetics (PK) of alectinib was assessed with physiologically based PK modeling prospectively and in a clinical study. An open‐label study (NCT02621047) investigated a single 300‐mg dose of alectinib in moderate (n = 8) and severe (n = 8) hepatic impairment (Child‐Pugh B/C), and healthy subjects (n = 12) matched for age, sex, and body weight. Physiologically based PK modeling was conducted prospectively to inform the clinical study design and support the use of a lower dose and extended PK sampling in the study. PK parameters were calculated for alectinib, its major similarly active metabolite, M4, and the combined exposure of alectinib and M4. Unbound concentrations were assessed at 6 and 12 hours postdose. Administration of alectinib to subjects with hepatic impairment increased the area under the plasma concentration–time curve from time 0 to infinity of the combined exposure of alectinib and M4 to 136% (90% confidence interval [CI], 94.7‐196) and 176% (90%CI 98.4‐315), for moderate and severe hepatic impairment, respectively, relative to matched healthy subjects. Unbound concentrations for alectinib and M4 did not appear substantially different between hepatic‐impaired and healthy subjects. Moderate hepatic impairment had only a modest, not clinically significant effect on alectinib exposure, while the higher exposure observed in severe hepatic impairment supports a dose adjustment in this population.
... The assumption of minor intestinal first-pass loss, which had been made in the preliminary model, was confirmed by these clinical data and will be reported separately. The effect of food on Alectinib Mechanistic Absorption Model Source: [16] a GastroPlus defaults for the fed and fasted states b A delay in the appearance of alectinib in the plasma was seen after dosing in the fed state and was captured with a lag time alectinib was then predicted with model 2. After comparison of model 2 simulations to clinical data from a food effect study [23], the solubility in the model was further refined so that simulations matched the clinical data producing model 3. This model was then used to extrapolate beyond the clinically tested situations to derive recommendations on the timing of alectinib administration with respect to meal intake. ...
... This model was then used to extrapolate beyond the clinically tested situations to derive recommendations on the timing of alectinib administration with respect to meal intake. Finally, the model was applied to predict the effect of gastric pH elevation on alectinib pharmacokinetics, and the prediction was compared to clinical data from a drug interaction study with esomeprazole [23]. ...
... The clinical studies used in this work are described in full elsewhere [21,22,23]. A high-level summary of these studies is given in Supplementary Material 1. ...
Alectinib, a lipophilic, basic, anaplastic lymphoma kinase (ALK) inhibitor with very low aqueous solubility, has received Food and Drug Administration-accelerated approval for the treatment of patients with ALK+ non-small-cell lung cancer. This paper describes the application of physiologically based absorption modeling during clinical development to predict and understand the impact of food and gastric pH changes on alectinib absorption. The GastroPlus™ software was used to develop an absorption model integrating in vitro and in silico data on drug substance properties. Oral pharmacokinetics was simulated by linking the absorption model to a disposition model fit to pharmacokinetic data obtained after an intravenous infusion. Simulations were compared to clinical data from a food effect study and a drug-drug interaction study with esomeprazole, a gastric acid-reducing agent. Prospective predictions of a positive food effect and negligible impact of gastric pH elevation were confirmed with clinical data, although the exact magnitude of the food effect could not be predicted with confidence. After optimization of the absorption model with clinical food effect data, a refined model was further applied to derive recommendations on the timing of dose administration with respect to a meal. The application of biopharmaceutical absorption modeling is an area with great potential to further streamline late stage drug development and with impact on regulatory questions.
... This finding is consistent with food effect studies showing no clinically meaningful effect of food on drug exposure for oral crizotinib [28], the second-generation oral ALK inhibitor brigatinib [29], the third-generation agent lorlatinib [30] and the ALK/ROS1 inhibitor entrectinib [31]. In contrast, food effect studies of the second-generation ALK TKIs alectinib Table 2 Bioavailability of SAF-189s following fasted versus fed administration AUC 0-∞ area under the plasma concentration-time curve from time 0 to infinity; AUC 0-t area under the plasma concentration-time curve from time 0 to last measurable concentration; CI confidence interval; C max maximum plasma drug concentration a One patient withdrew from the study following fasted administration of SAF-189s [32,33] and ceritinib [34] showed a positive effect of administration with food, and the labelling for these drugs therefore recommends administration with food. Interestingly, although SAF-189s was developed based on ceritinib, it appears to have a differential food effect. ...
... For example, no effect of food on PK and safety profiles was observed for crizotinib (BCS class IV) [28], brigatinib (BCS class I) [29], lorlatinib (BCS class IV) [30] or entrectinib (BCS class II) [31], and their respective labelling indicates administration with or without food. Conversely, compared with fasted administration, alectinib (BCS class IV) taken with food showed improved exposure with no effect on safety [32,33] and ceritinib (BCS class IV) showed improved exposure and safety with food [34]. Both alectinib and ceritinib suggest administration with food in their labels. ...
This study was conducted to investigate the effect of high-fat meals on the pharmacokinetics (PK) and safety profile of SAF-189s, a novel ALK/ROS1 inhibitor.
This was a single-center, phase I, open-label, crossover study in which healthy adults (≥18 years) were randomized (1:1) to two sequences of SAF-189s administration (fasted-fed or fed-fasted) separated by a 14-day washout. After a ≥10-h overnight fast, volunteers received SAF-189s 160 mg orally in a fasted state or 30 min after a high-fat, high-calorie meal. Similarity of pharmacokinetic parameters was concluded if the 90% CI for the geometric mean ratio (GMR) between the fed and fasted group fell within the predefined range of 0.80–1.25.
In total, 24 subjects were enrolled and 23 completed the study. SAF-189s maximum plasma concentration (Cmax; GMR: 109.1% [90% CI 103.1–115.4]) was comparable under fed (high-fat meal, n = 24) versus fasted (n = 23) conditions, with no effect on area under the plasma concentration–time curve from time 0 to t (AUC0-t; GMR: 105.1% [90% CI 100.3–110.2]) and AUC from time 0 to infinity (AUC0-∞; GMR: 105.5% [90% CI, 100.6–110.6]). In both groups, the median time to maximum plasma concentration (tmax) was around 6 h and mean plasma half-life (t½) was around 35 h. Fed administration led to a lower incidence of treatment-emergent adverse events (TEAEs; 29.2% vs 54.2%), including gastrointestinal disorders (4.2% vs 41.7%) and headache (0.0% vs 12.5%), versus fasted administration.
A high-fat meal had minimal effect on the pharmacokinetic profile of SAF-189s compared with a fasted state following a single dose of 160 mg. Administration with a high-fat meal led to a lower incidence of TEAEs.
... The impaired bioavailability of AH has been attributed to its low aqueous solubility in aqueous buffers and moderate in vitro permeability, which results in incomplete absorption of AH from the clinical formulation [2][3][4][5]. Interestingly, the solubility of AH is substantially higher in fed-state simulated intestinal fluid (FeSSIF) than in fasted-state simulated intestinal fluid (FaSSIF), thus, indicating a surfactant-oriented drug solubility [6]. This improved solubility led to an approximately 3fold increase in systemic exposure of AH when co-administrated with a high-fat meal (fed state) as compared to a fasting state [3,7]. ...
... This improved solubility led to an approximately 3fold increase in systemic exposure of AH when co-administrated with a high-fat meal (fed state) as compared to a fasting state [3,7]. Due to its poor bioavailability, the recommended dose of AH is quite high i.e., 600 mg (4 x 150 mg capsule) twice daily taken along with food to meet clinical efficacy [6,7]. Thus, addressing the solubility concern is the first and foremost challenge for a formulator in the development of an immediate-release solid dosage form [8]. ...
Objective: Alectinib hydrochloride (AH), a poorly soluble drug, exhibits low solubility thereby very low bioavailability. The present study aims to develop and optimize surface-modified solid dispersion of AH (AH-SMSD) with enhanced solubility and dissolution using Soluplus® (SOL) and Gelucire 44/14 (GEL) as a polymer and surfactant, respectively. Methods: Design of Experiments (DoE) was implemented to optimize the weight ratio of SOL (X1), and GEL (X2), keeping the drug weight constant to maximize the solubility (Y1) and dissolution (Y2). The optimized solid dispersion was subjected to solubility and dissolution in bio-relevant media and characterized using differential scanning calorimetry (DSC), Powder X-ray diffraction (pXRD), Fourier-transform infrared (FTIR), and scanning electron microscopy (SEM). Results: A statistically significant model is obtained for solubility and dissolution through DoE. Formulation (F9) containing AH: SOL: GEL in weight ratios 1:5:5 showed a 547-fold increase in solubility. This solubility enhancement further translated into dissolution improvement with drug release of >80% in 15 min. The optimized formulation also showed improved solubility and dissolution in fasted-state bio-relevant media. DSC and pXRD showed a change in the crystallinity pattern of the drug. FTIR showed the existence of weak intermolecular interactions. Morphological evaluation through SEM demonstrated that the drug particles were dispersed to a hydrophilic carrier matrix, thus, transforming the hydrophobic drug into a hydrophilic form. Conclusion: AH-SMSD with enhanced solubility and dissolution was successfully developed. The optimized formulation also showed improvement in the bio-relevant media and therefore has the potential to improve in vivo oral bioavailability (however, needs to be experimentally explored).
... Alectinib is a BCS class II drug with a low extraction ratio of 0.14 that displays a significant food effect [80]. In the presence of a high-fat meal, alectinib AUC and Cmax increases 3.11-fold and 3.31fold respectively compared with fasted conditions [81]. Its solubility increases from 23 μg/mL in FaSSIF at pH 6.5 to 77 μg/mL in FeSSIF at pH 5 [81]. ...
... In the presence of a high-fat meal, alectinib AUC and Cmax increases 3.11-fold and 3.31fold respectively compared with fasted conditions [81]. Its solubility increases from 23 μg/mL in FaSSIF at pH 6.5 to 77 μg/mL in FeSSIF at pH 5 [81]. Thus, alectinib absorption is dependent on bile salts released during digestion that enhance drug solubility. ...
Purpose
This review summarizes the development processes of hepatic impairment (HI) PBPK models, examines current challenges, and proposes potential solutions.
Recent Findings
Because hepatic impairment can significantly alter a patient’s physiology, HI PBPK models must consider complex in vivo processes leading to potential changes in PK parameters. Adjustments need to be made to absorption, distribution, metabolism, and elimination parameters. Multiple studies already include changes in levels of CYP enzymes, UGTs, transporters, shunting, and protein binding in their HI models. However, despite recent progress, HI PBPK models face multiple challenges and may overpredict drug exposure with increasing severity of liver dysfunction. Foremost among these challenges is the use of the Child–Pugh scoring system in designing HI PBPK models. Furthermore, most HI PBPK models do not account for changes in certain drug parameters, potentially skewing resulting predictions. Ultimately, limitations with PBPK models can be traced to the scarcity of existing HI PBPK models and clinical data. Filling in this knowledge gap is critical to best support safe drug dosing adjustments for hepatically impaired patients.
Summary
Recent advancements have enhanced the predictive power of HI PBPK models, enabling accurate reflections of clinical trials. However, significant obstacles in developing accurate PK predictions remain, especially for severe impairment.
... Exposure to abiraterone, alectinib, cabozantinib, pazopanib and sunitinib and the observed interpatient variability within each group is likely to be influenced to a greater extent by factors other than body weight, as no correlation was observed for these oral oncolytics. For abiraterone and alectinib, food effects probably have a greater influence on plasma levels, whereas for pazopanib, the variable absorption probably plays an important role on the total exposure [35][36][37]. ...
Purpose
Data on the effects of obesity on drug exposure of oral targeted oncolytics is scarce. Therefore, the aim of this study was to investigate the influence of body weight and body mass index (BMI) on trough levels of oral oncolytics with an exposure–response relationship. The oral oncolytics of interest were abiraterone, alectinib, cabozantinib, crizotinib, imatinib, pazopanib, sunitinib and trametinib.
Methods
This retrospective cohort study included patients treated with the selected oral oncolytics at the standard dose, with a measured trough level at steady state and with available body weight. The Spearman’s correlation test was used to determine the correlation between body weight and trough levels. The Fisher’s exact text was used to compare the frequency of inadequate trough levels between BMI categories.
Results
1265 patients were included across the different oral oncolytics. A negative correlation coefficient was observed between weight and trough levels for crizotinib (n = 75), imatinib (n = 201) and trametinib (n = 310), respectively, ρ = − 0.41, ρ = − 0.24 and ρ = − 0.23, all with a p-value < 0.001. For crizotinib, a higher percentage of patients with a body weight > 100 kg had inadequate trough levels. No statistically significant differences were observed in the frequency of inadequate trough levels between BMI categories.
Conclusion
Higher body weight was only correlated with lower plasma trough levels for crizotinib, imatinib, and trametinib. Therefore, patients with a high body weight may require dose escalation to obtain adequate target levels when treated with these oral oncolytics.
... To date, several ALK-TKIs have been developed and are widely available in clinical practice, some of which have received approval by the US Food and Drug Administration (FDA), such as alectinib. Coadministration of esomeprazole (Morcos et al. 2017c), and posaconazole (a strong CYP3A inhibitor) (Morcos et al. 2017a) had no clinically relevant effect on the exposure of alectinib and M4 in humans. However, CYP inhibitors and inducers can significantly alter the exposure of ALK-TKIs and can lead to clinically relevant DDI (Zhao et al. 2020). ...
In this study, the effects of 17 CYP3A4 variants and drug-drug interactions (DDI) with its mechanism on alectinib metabolism were investigated. In vitro incubation systems of rat liver microsomes (RLM), human liver microsomes (HLM) and recombinant human CYP3A4 variants were established. The formers were used to screen potential drugs that inhibited alectinib metabolism and study the underlying mechanism, and the latter was used to determine the dynamic characteristics of CYP3A4 variants. Alectinib and its main metabolite M4 were quantitatively determined by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The results showed that compared with CYP3A4.1, only CYP3A4.29 showed higher catalytic activity, while the catalytic activity of CYP3A4.4, .7, .8, .12, .14, .16, .17, .18, .19, .20, .23, and .24 decreased significantly. Among them, the catalytic activity of CYP3A4.20 is the lowest, only 2.63% of that of CYP3A4.1. Based on the RLM incubation system in vitro, 81 drugs that may be combined with alectinib were screened, among which 18 drugs had an inhibition rate higher than 80%. In addition, nicardipine had an inhibition rate of 95.09% with a half-maximum inhibitory concentration (IC50) value of 3.54 ± 0.96 μM in RLM and 1.52 ± 0.038 μM in HLM, respectively. There was a mixture of non-competitive and anti-competitive inhibition of alectinib metabolism in both RLM and HLM. In vivo experiments of Sprague–Dawley (SD) rats, compared with the control group (30 mg/kg alectinib alone), the AUC(0–t), AUC(0–∞), Tmax and Cmax of alectinib administered in combination with 6 mg/kg nicardipine were significantly increased in the experimental group. In conclusion, the metabolism of alectinib was affected by polymorphisms of the CYP3A4 gene and nicardipine. This study provides reference data for clinical individualized administration of alectinib in the future.
... [4][5] Macros et al. conducted a human investigation in healthy volunteers who were administered with ALK and esomeprazole in fasted and fed settings to study the clinical impact of acidreducing agents (ARA) and the possibility of interaction and modifications in the pharmacokinetic pathway. 6 Although numerous in-silico modeling strategies, as well as human studies, are designed for drug-interaction prediction based on physiochemical data that have been documented, a simple, sensitive, and reliable experimental method will be favored for a better understanding and identification of the prospective risk of interaction. [7][8] In this study, the effect of pH on the target drug due to pH modulation because of administration of proton pump inhibitors in the stomach and intestine was investigated using an in vitro micro dissolution experiment. ...
... Several studies have investigated the DDIs between PPIs and TKIs; the results are contradictory concerning PPI interaction with the bioavailability and activity of TKIs. A summary of these DDIs is presented in Table 3 (Rugo et al., 2005;Egorin et al., 2009;Yin et al., 2010;Yin et al., 2012;Takahashi et al., 2012;Hilton et al., 2013;Abbas et al., 2013;Musib et al., 2013;Tan et al., 2013;Johansson et al., 2014;Narasimhan et al., 2014;Chu et al., 2015;Kletzl et al., 2015;Ha et al., 2015;Iurlo et al., 2016;Kumarakulasinghe et al., 2016;Lam et al., 2016;Zenke et al., 2016;Chu et al., 2017;Lalani et al., 2017;Lacy et al., 2017;Lau et al., 2017;Morcos et al., 2017;Yokota et al., 2017;de Jong et al., 2018;Nieves Sedano et al., 2018;Ohgami et al., 2018;Fang et al., 2019;Mir et al., 2019;Vishwanathan et al., 2018;Pisano et al., 2019;de Man et al., 2019;Koutake et al., 2020;Ruanglertboon et al., 2020;Van De Sijpe et al., 2020;Chen et al., 2021;Rassy et al., 2021). Table 4 summarizes the main studies reporting reductions in the survival of patients receiving this combination of medication Ha et al., 2015;Fang et al., 2019;Mir et al., 2019). ...
Background: Proton pump inhibitors (PPIs) are one of the most widely used drugs worldwide and are overprescribed in patients with cancer; there is increasing evidence of their effects on cancer development and survival. The objective of this narrative review is to comprehensively identify cancer medications that have clinically meaningful drug–drug interactions (DDIs) with PPIs, including loss of efficacy or adverse effects, and to explore the association between PPIs and cancer.
Methods: A PubMed search of English language studies published from 1 January 2016, to 1 June 2021 was conducted. The search terms included “proton pump inhibitors,” “cancer,” “chemotherapy,” “immunotherapy,” “hormonotherapies,” “targeted therapies,” “tyrosine kinase inhibitors,” and “gut microbiome”. Recent and relevant clinical trials, meta-analyses, and reviews were included.
Results: PPIs may have pro-tumor activity by increasing plasma gastrin levels or anti-tumor activity by inhibiting V-ATPases. However, their impact on cancer survival remains unclear. PPIs may decrease the efficacy of some antineoplastic agents through direct DDIs (e.g., some tyrosine kinase inhibitors, capecitabine, irinotecan, methotrexate). More complex DDIs seem to exist for immunotherapies with indirect interactions through the microbiome. PPIs worsen hypomagnesemia, bone loss, iron, and vitamin B12 deficiencies but may have a protective effect on the renal system.
Discussion/Conclusions: PPIs may interact with the cancer microbiome and the efficacy of various antineoplastic agents, although only a few DDIs involving PPIs are clinically significant. Further pharmaco-epidemiological studies are warranted, but physicians should be aware of the potential consequences of PPI use, which should be dose appropriate and prescribed according to guidelines.
... In a study with healthy subjects, coadministration of esomeprazole and alectinib had no relevant effect on the exposure of the latter [51]. No studies are currently available regarding concomitant use of brigatinib and PPIs. ...
Proton pump inhibitors (PPIs) are the most commonly used anti-acid drugs worldwide, including among cancer patients. However, drug-drug interactions between PPIs and other agents may lead to decreased drug absorption with possible reduced therapeutic benefit, or even increased toxicity. Unfortunately, only scarce data exist regarding the safety of concomitant PPI use with anti-cancer agents. We aim at reviewing current evidence on this possible interaction by dividing anti-cancer agents by class. Until further data is available, we encourage healthcare providers to limit unnecessary PPI overuse.
... This could be caused by the substantial food effect of alectinib, as its exposure increases more than fourfold when administered with a high-fat meal compared with fasting conditions. 16 According to the label, alectinib is administered concomitantly with food, but the content and volume of these meals could vary substantially within patients over time. ...
Crizotinib and alectinib are anaplastic lymphoma kinase (ALK)‐inhibitors indicated for the treatment of ALK‐positive metastatic non‐small‐cell lung cancer (NSCLC). At the currently used fixed doses, interindividual variability in exposure is high. The aim of this study was to investigate whether minimum plasma concentrations (Cmin) of crizotinib and alectinib are related to efficacy and toxicity. An observational study was performed, in which ALK‐positive NSCLC patients were included who were treated with crizotinib or alectinib and of whom pharmacokinetic samples were collected in routine care. Exposure‐response analyses were explored using previously proposed Cmin thresholds of 235 ng/mL for crizotinib and 435 ng/mL for alectinib. Forty‐eight crizotinib and 52 alectinib patients were included. For crizotinib, median progression‐free survival (mPFS) was 5.7 vs. 17.4 months for patients with Cmin < 235 ng/mL (48%) and ≥ 235 ng/mL, respectively (p=0.08). In multivariable analysis, Cmin < 235 ng/mL resulted in a hazard ratio (HR) of 1.79 (95%CI 0.90–3.59, p=0.100). In a pooled analysis of all crizotinib patients (not only ALK‐positive, n=79), the HR was 2.15 (95%CI 1.21–3.84, p=0.009). For alectinib, mPFS was 12.6 months vs. not reached (95%CI 19.8–NA) for patients with Cmin < 435 ng/mL (37%) and ≥ 435 ng/mL, respectively (p=0.04). Multivariable analysis resulted in a HR of 4.29 (95%CI 1.33–13.90, p=0.015). In conclusion, PFS of crizotinib and alectinib treated NSCLC patients is prolonged in patients with Cmin ≥ 235 ng/mL and 435 ng/mL, respectively. Therefore, therapeutic drug monitoring should be part of routine clinical management for these agents.
... coadministration. 29 By contrast, using our previous preliminary decision framework would incorrectly predict that alectinib may have a positive DDI with ARAs. Overall it seems that PBPK models, with proper verification, could generally provide correct prediction on the lack of pH-dependent DDI. ...
Weak base drugs (WBDs) are susceptible to drug‐drug interactions (DDIs) when co‐administered with gastric acid reducing agents (ARAs). We developed PBPK models to evaluate the potential of such pH‐dependent DDIs for 4 WBDs, i.e., tapentadol, darunavir, erlotinib, and saxagliptin. The PBPK models of these drugs were first optimized using PK data following oral administration without ARAs, which were then verified with data from additional PK studies in the presence and absence of food. The models were subsequently utilized to predict the extent of DDIs with ARA co‐administration. Sensitivity analysis was conducted to explore the impact of gastric pH on quantitative prediction of drug exposure in the presence of ARA. The results suggested that the PBPK models developed could adequately describe the lack of the effect of ARA on the PK of tapentadol, darunavir, and saxagliptin, and could qualitatively predict the effect of ARA in reducing the absorption of erlotinib. Further studies involving more drugs with positive pH‐dependent DDIs are needed to confirm the findings and broaden our knowledge base to further improve the utilization of PBPK modeling to evaluate pH‐dependent DDI potential.
... Owing to the positive food effect, a lower dose could be given compared to the fasted state. 49,50 A similar approach to ceritinib was adopted by Morcos et al. 9 who investigated the effect of food and esomeprazole (PPI) on the alectinib pharmacokinetics. Alectinib is a weak base with a known positive food effects and with a predicted reduction in absorption in the presence of ARAs/PPIs. ...
Advances in understanding of human disease have prompted the U.S. Food and Drug Administration to classify certain molecules as “break-through therapies,” providing an accelerated review that may potentially enhance the quality of patient lives. With this designation come compressed timelines to develop drug products, which are not only suitable for clinic trials but can also be approved and brought to the market rapidly. Early risk identification for decreased oral absorption due to drug-drug interactions with proton pump inhibitors (PPIs) or acid-reducing agents (ARAs) is paramount to an effective drug product development strategy. An early ARA/PPI drug-drug interaction (DDI) risk identification strategy has been developed using physiologically based absorption modeling that readily integrates ADMET predictor generated in silico estimates or measured in vitro solubility, permeability, and ionization constants. Observed or predicted pH-solubility profile data along with pKas and drug dosing parameters were used to calculate a fraction of drug absorbed ratio in absence and presence of ARAs/PPIs. An integrated physiologically based pharmacokinetic absorption model using GastroPlus™ with pKa values fitted to measured pH-solubility profile data along with measured permeability data correctly identified the observed ARA/PPI DDI for 78% (16/22) of the clinical studies. Formulation strategies for compounds with an anticipated pH-mediated DDI risk are presented.
... Therefore, the combined exposure of alectinib and M4 (alectinib + M4) steady-state trough concentration adjusted for the individual molecular weights was utilized as the overall alectinib exposure measure (herein C trough,ss ) in the exposure-response analyses. This approach has been utilized for all other alectinib exposure investigations [22][23][24][25] and similarly utilized for exposure-response assessments for other agents with active metabolites [26][27][28]. ...
Purpose:
Alectinib is a selective and potent anaplastic lymphoma kinase (ALK) inhibitor that is active in the central nervous system (CNS). Alectinib demonstrated robust efficacy in a pooled analysis of two single-arm, open-label phase II studies (NP28673, NCT01801111; NP28761, NCT01871805) in crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC): median overall survival (OS) 29.1 months (95% confidence interval [CI]: 21.3-39.0) for alectinib 600 mg twice daily (BID). We investigated exposure-response relationships from final pooled phase II OS and safety data to assess alectinib dose selection.
Methods:
A semi-parametric Cox proportional hazards model analyzed relationships between individual median observed steady-state trough concentrations (Ctrough,ss) for combined exposure of alectinib and its major metabolite (M4), baseline covariates (demographics and disease characteristics) and OS. Univariate logistic regression analysis analyzed relationships between Ctrough,ss and incidence of adverse events (AEs: serious and Grade ≥ 3).
Results:
Overall, 92% of patients (n = 207/225) had Ctrough,ss data and were included in the analysis. No statistically significant relationship was found between Ctrough,ss and OS following alectinib treatment. The only baseline covariates that statistically influenced OS were baseline tumor size and prior crizotinib treatment duration. Larger baseline tumor size and shorter prior crizotinib treatment were both associated with shorter OS. Logistic regression confirmed no significant relationship between Ctrough,ss and AEs.
Conclusion:
Alectinib 600 mg BID provides systemic exposures at plateau of response for OS while maintaining a well-tolerated safety profile. This analysis confirms alectinib 600 mg BID as the recommended global dose for patients with crizotinib-resistant ALK-positive NSCLC.
... 20 Similarly, concomitant adminis-tration with esomeprazole had negligible effects on alectinib or M4. 21 Mild hepatic impairment, renal impairment (creatinine clearance of >30 mL/ min), age, body weight, and sex do not appear to affect alectinib pharmacokinetics; however, the effects of severe renal or hepatic impairment have not been studied. 4 The effects of chronic hepatic impairment on the pharmacokinetics of alectinib are currently being studied (ClinicalTrials.gov ...
Purpose:
The pharmacology, pharmacokinetics, clinical efficacy, safety and tolerability, dosage and administration, and place in therapy of alectinib for treatment of patients with non-small-cell lung cancer (NSCLC) are reviewed.
Summary:
In patients with NSCLC driven by mutations ofALK, the gene coding for anaplastic lymphoma kinase (ALK), treatment with the ALK inhibitor crizotinib has been found to provide median progression-free survival (PFS) of 10.9 months; however, therapeutic failures and tumor progression to brain metastases are common with crizotinib use, prompting research to find more potent and tolerable ALK inhibitors that target major oncogenic drivers of NSCLC. Alectinib is a next-generation ALK inhibitor initially approved by the Food and Drug Administration for use in patients with metastaticALK-positive NSCLC who are intolerant of or have disease progression during crizotinib therapy. In clinical trials, alectinib was found effective for delaying disease progression and, more importantly, reducing brain metastases in patients with NSCLC who developed resistance or intolerance to previous crizotinib therapy. Published data from clinical trials indicate that the most common grade 1 and 2 adverse effects associated with alectinib use are fatigue, constipation, peripheral edema, and myalgia; the most common grade 3 or 4 reactions include increases in creatine phosphokinase, alanine aminotransferase, and aspartate aminotransferase levels.
Conclusion:
Alectinib appears to be effective and safe for use in patients with metastaticALK-positive NSCLC, with demonstrated superiority over crizotinib in terms of PFS rates. Research to better define ALK inhibitor resistance mechanisms and alectinib's place in therapy is ongoing.
... On the other hand, reduced drug BA can lead to ineffectiveness. Warfarin and Alectinib, an anaplastic lymphoma kinase (ALK) inhibitor, are two examples of medication for which food intake must be considered (Hornsby et al., 2008;Morcos et al., 2017). Therefore, the FDA recommends that the food-effect study should be performed, to determine the maximal efficacy with the presence of diet in the gastrointestinal tract for investigational new drugs (INDs). ...
Background and Objectives: Ginsenoside compound K (CK) is a candidate drug for rheumatoid arthritis therapy. This clinical trial was designed to evaluate the effects of food and sex on the pharmacokinetics of CK and its metabolite 20(S)-protopanaxadiol (PPD).
Methods: An open-label, single-center, two-period crossover trial was performed in healthy Chinese subjects (n = 24; male = 12, female = 12), randomized to either the fasting overnight or the high-fat meal group before a single 200 mg dose of monomer CK was administered. According to the concentration-time data of plasma and urine samples from each subject, the pharmacokinetic parameters of CK and 20(S)-PPD were calculated and statistically analyzed.
Results: A two-way ANOVA test combined with mean plots showed no statistically significant interaction between food and sex. High-fat meal accelerated the absorption of CK, with tmax being shortened from 3.6 to 2.5 h (p = 0.015). In contrast, food significantly increased the Cmax, AUClast, and AUCinf(p < 0.001) with the 90% confidence intervals falling outside of the conventional 0.80–1.25. Females had higher exposure levels of CK than males, but the difference was statistically significant only after a high-fat meal. Of note, CK was rarely excreted in urine. Furthermore, the effects of food and sex were also observed on 20(S)-PPD.
Conclusion: High-fat food and sex both had an impact on the disposition of CK in vivo, but rather than a significant interaction effect. High-fat food accelerated and increased the absorption of CK, while the exposure of CK was higher in females compared to males. The results indicate that food and sex should be two noteworthy factors in future research on CK.
This study aims to improve the solubility and dissolution rate of alectinib (ALB), a tyrosine kinase inhibitor commonly used for treating non-small-cell carcinoma (NSCLC). Given ALB’s low solubility and bioavailability, complexation with β-cyclodextrin (βCD) and hydroxy propyl β-cyclodextrin (HPβCD) was evaluated. Some of the different preparation methods used with varying ALB-to-CD ratios led to the formation of complexes that were characterized using Fourier-Transform Infrared (FTIR) techniques and Differential Scanning Calorimetry (DSC) to prove complex formation. The encapsulation efficiency was also determined. The simulations were carried out for ALB’s interactions with βCD and HPβCD. This study identified the most soluble complex (ALB–HPβCD; 1:2 ratio) and evaluated its dissolution. The bioavailability of the ALB–HPβCD complex was evaluated in Wistar rats relative to free ALB. Pharmacokinetic profiles revealed increased Cmax (240 ± 26.95 ng/mL to 474 ± 50.07 ng/mL) and AUC0-48 (5946.75 ± 265 ng.h/mL to 10520 ± 310 ng.h/mL) with no change in the elimination rate constant. In conclusion, the complexation of ALB–HPβCD manages to increase in vitro solubility, the dissolution rate, and oral bioavailability, providing a favorable approach to improving ALB administration.
Tyrosine kinase inhibitors (TKI) have introduced a significant advancement in cancer management. These compounds are administered orally, and their absorption holds a pivotal role in determining their variable efficacy. They exhibit extensive distribution within the body, binding strongly to both plasma and tissue proteins. Often reliant on efflux and influx transporters, TKI undergo primary metabolism by intestinal and hepatic cytochrome P450 enzymes, with non-kidney clearance being predominant. Due to their limited therapeutic window, many TKI display considerable intra- and interindividual variability. This review offers a comprehensive analysis of the clinical pharmacokinetics of TKI, detailing their interactions with drug transporters and metabolic enzymes, while discussing potential clinical implications. The prevalence of kidney conditions, such as acute kidney injury (AKI) and chronic kidney disease (CKD), among cancer patients is explored in terms of their impact on TKI pharmacokinetics. Lastly, the potential nephrotoxicity associated with TKI is also examined.
Backgrounds: Brain metastases occur in approximately 30% of patients with non-small-cell lung cancer (NSCLC). Therefore, the free drug concentration in cerebrospinal fluid (CSF) is strongly associated with the clinical efficacy.
Purpose: The present study aimed to develop physiologically based pharmacokinetic (PBPK) models that can predict the steady-state trough concentration (Ctrough) in plasma and CSF, as well as anaplastic lymphoma kinase (ALK) occupancy (AO), for three inhibitors: crizotinib (CRI), alectinib (ALE), and lorlatinib (LOR).
Methods: To achieve this, population PBPK models were successfully developed and validated using multiple clinical pharmacokinetics (PK) and drug–drug interaction (DDI) studies, both in healthy subjects and patients.
Results: The prediction-to-observation ratios for plasma AUC, Cmax, and Ctrough in heathy subjects and patients ranged between 0.5 and 2.0. In addition, PK profiles of CRI, ALE, and LOR in CSF aligned well with observed data. Moreover, the AUC and Cmax ratios of the three inhibitors when co-administered with CYP3A4 inhibitors/inducers also matched with clinically observed values. Utilizing PK thresholds for effective plasma Ctrough and AO values on wild-type and four ALK mutations in plasma and CSF, PBPK models were then combined with the mean and 95% confidence interval to predict optimal dosing regimens.
Conclusions: Overall, these PBPK models provide valuable insights into determining appropriate dosing regimens for the three ALK inhibitors, understanding their effectiveness in brain metastasis therapy, and analyzing the underlying mechanisms of on-target resistance.
The traditional design of food‐effect studies has a high patient burden for toxic drugs with long half‐lives (e.g., anticancer agents). Microtracers could be used to assess food‐effect in patients without influencing their ongoing treatment. The feasibility of a microtracer food‐effect study during steady‐state of the therapeutic drug was investigated in an in silico simulation study with alectinib as an example for a relative toxic drug with a long half‐life. Microtracer pharmacokinetics were simulated based on a previously published population pharmacokinetic model and used for estimation of a model with and a model without food as a covariate on oral bioavailability of alectinib (assuming a 40% food‐effect). Power was defined as the fraction of clinical trials where a significant ( p < 0.01) food‐effect was identified. The proposed study design of 10 patients on steady‐state treatment, 10 blood samples collected within 24 h after administration and an assumed food‐effect of 40% had a power of 99.9%. The mean estimated food‐effect was 39.8% (80% confidence interval: 31.0%–48.6%). The feasibility of microtracer food‐effect studies was demonstrated. The design of the microtracer food‐effect study allowed estimation of the food‐effect with minimal influence on therapeutic treatment and reducing patient burden compared to the traditional study design for toxic drugs with long half‐lives.
Oral extended-release (ER) dosage forms have been used to sustain blood drug levels, reduce adverse events, and improve patient compliance. We investigated potential effect of comedication on pharmacokinetic exposure of nifedipine ER products with different formulation designs and manufacturing processes. A clinical study compared a generic version of nifedipine ER tablet with pH-dependent dissolution behavior with an osmotic pump product with pH independent drug release under fasting condition. In this study, two nifedipine tablet products were tested with or without short term omeprazole comedication in healthy subjects. Seven-day administration of omeprazole before nifedipine dosing significantly increased the gastric pH, and subsequently increased the geometric least square (LS) means of AUC0-t and Cmax of nifedipine to 132.6% (90% CI 120.6%-145.7%) and 112.8% (90% CI 100.8%-126.3%) for pH-dependent ER tablets, and 120.6% (90% CI 109.7%-132.5%) and 122.5% (90% CI 113.7%-131.9%) for the pH-independent ER tablets, respectively. Similar extent of increase in AUC0-t and Cmax was confirmed in the subpopulations whose gastric pH was ≥ 4 or ≤ 3 in subjects with or without omeprazole administration. Given that similar increases in drug exposures were observed for both pH-dependent and pH-independent nifedipine formulations and the geometric LS mean ratios were between 112 and 133% with and without short term omeprazole comedication, the gastric pH may have limited effects on omeprazole-induced nifedipine PK changes on the tested formulations. The inhibition of cytochrome P450 3A4 activity may play a significant role causing nifedipine exposures change for both formulations, which would warrant additional assessment.
Alectinib, approved as 150 mg capsules for the treatment of adults with advanced ALK-positive non-small-cell lung cancer, is being assessed in children with ALK-positive solid and central nervous system tumors. An ad hoc pediatric-friendly suspension of alectinib, prepared from capsule contents, is under investigation as an alternative formulation for children who cannot swallow capsules. This randomized, cross-over, relative bioavailability and food effect study evaluated alectinib administered as an oral suspension vs. the capsule following conventional venipuncture and capillary microsampling. A total of 28 healthy adult subjects received a 600 mg single dose of alectinib in two groups: fasted (n = 14) and mixed fed (n = 14; seven receiving high-fat meal and seven receiving low-fat meal). Combined alectinib + M4 exposure was higher for suspension vs. capsule, with geometric mean ratio (GMR) of 2.6 for area under the concentration-time curve extrapolated to infinity (AUC0-∞ ) and 3.0 for maximum observed concentration (Cmax ) under fasted conditions, and 1.7 for both parameters for mixed fed. The suspension showed increased alectinib + M4 AUC0-∞ following a high-fat meal vs. fasted conditions (GMR 1.7 [90% confidence interval (CI) 1.4-2.2]). Alectinib AUC0-∞ and Cmax measured in venous and capillary samples were generally similar for the suspension and capsule. Single oral doses of 600 mg alectinib suspension and capsule were well tolerated, with no safety concerns. Based on these findings, the oral suspension of alectinib appears suitable for use in pediatric studies after appropriate dose adjustment relative to the capsule.
Several regulatory guidances on the use of physiologically based pharmacokinetic (PBPK) analyses and physiologically based biopharmaceutics model(s) (PBBM(s)) have been issued. Workshops are routinely held, demonstrating substantial interest in applying these modeling approaches to address scientific questions in drug development. PBPK models and PBBMs have remarkably contributed to model-informed drug development (MIDD) such as anticipating clinical PK outcomes affected by extrinsic and intrinsic factors in general and specific populations. In this review, we proposed practical considerations for a “base” PBPK model construction and development, summarized current status, challenges including model validation and gaps in system models, and future perspectives in PBPK evaluation to assess a) drug metabolizing enzyme(s)- or drug transporter(s)- mediated drug-drug interactions b) dosing regimen prediction, sampling timepoint selection and dose validation in pediatric patients from newborns to adolescents, c) drug exposure in patients with renal and/or and hepatic organ impairment, d) maternal–fetal drug disposition during pregnancy, and e) pH-mediated drug-drug interactions in patients treated with proton pump inhibitors/acid-reducing agents (PPIs/ARAs) intended for gastric protection. Since PBPK can simulate outcomes in clinical studies with enrollment challenges or ethical issues, the impact of PBPK models on waivers and how to strengthen study waiver is discussed.
Food effect (FE) and gastric pH-dependent drug-drug interactions (DDIs) are both absorption-related. Here, we evaluated if Biopharmaceutics Classification System (BCS) classes may be correlated with FE or pH-dependent DDIs. Trends in FE data were investigated for 170 drugs with clinical FE studies from the literature and new drugs approved from 2013 to 2019 by US Food and Drug Administration. A subset of 38 drugs was also evaluated to determine whether FE results can inform the need for a gastric pH-dependent DDI study. The results of FE studies were defined as no effect (AUC ratio 0.80–1.25), increased exposure (AUC ratio ≥1.25), or decreased exposure (AUC ratio ≤0.8). Drugs with significantly increased exposure FE (AUC ratio ≥2.0; N=14) were BCS Class 2 or 4, while drugs with significantly decreased exposure FE (AUC ratio ≤0.5; N=2) were BCS Class 1/3 or 3. The lack of FE was aligned with the lack of a pH-dependent DDI for all 7 BCS Class 1 or 3 drugs as expected. For the 13 BCS Class 2 or 4 weak base drugs with an increased exposure FE, 6 had a pH-dependent DDI (AUC ratio ≤0.8). Among the 16 BCS Class 2 or 4 weak base drugs with no FE, 6 had a pH-dependent DDI (AUC ratio ≤0.8). FE appears to have limited correlation with BCS classes except for BCS Class 1 drugs, confirming that multiple physiological mechanisms can impact FE. Lack of FE does not indicate absence of pH-dependent DDI for BCS Class 2 or 4 drugs.
Graphical Abstract
Ensartinib is a promising, aminopyridazine‐based small molecule that potently inhibits anaplastic lymphoma kinase. This random, two‐period, crossover study evaluated the effects of food on the pharmacokinetics of ensartinib after a single dose (225 mg) in healthy Chinese subjects. The pharmacokinetic parameters of ensartinib were calculated using non‐compartmental analysis. Twenty‐four Chinese healthy subjects aged 20–44 years were included in this study. The area under the concentration–time curve of ensartinib was approximately 25% lower after the intake of a high‐fat, high‐calorie meal prior to dosing, whereas the maximum plasma concentration was decreased by approximately 37%, illustrating the statistically significant effect of food on ensartinib pharmacokinetics. In addition, food intake prolonged the absorption phase of ensartinib (median time to maximum plasma concentration, from 4.5 to 6 h). Population pharmacokinetic (PopPK) analysis was conducted using NONMEM, and the influences of food, age, sex, body weight, and body mass index were studied via covariate analysis. In this analysis, ensartinib plasma concentrations were best described by a one‐compartment model with Weibull absorption. The final model included food and age as covariates on apparent distribution and apparent clearance. Based on the final PopPK model, food was identified as a significant covariate for apparent clearance, apparent volume of distribution, and absorption rate constant, consistent with the results of non‐compartmental pharmacokinetic analysis.
Bromelain, the aqueous extract of pineapple, has been used as a food supplement with reported nutritional and therapeutic benefits. Bromelain has anti-cancer, anti-inflammatory, antithrombotic, and fibrinolytic effects. Anaplastic lymphoma kinase (ALK) inhibitors, including alectinib (ALC), ceritinib (CER), and crizotinib (CRZ), have been efficiently used in the management of non-small cell lung cancer (NSCLC). The solubility of ALC, CER, and CRZ is much higher at low acidic pH (pH 1) and it decreases as the pH increases affecting their absorption with a subsequent decrease in their bioavailability. It was thought that the intake of bromelain could result in a decrease in the bioavailability of ALC, CER, and CRZ due to bromelain-induced alkalizing effect following digestion. On the contrary, bromelain could possibly increase plasma exposure of the cited drugs due to its known muco-permeation enhancing effect. The therapeutic-anticancer effect of bromelain can be possibly increased/enhanced with concomitant intake of other anticancer medications or it can add to the value of food supplements for its known nutritional benefits. Thus, this work aims at studying the possibility of any PK interaction when bromelain was taken while on ALC/CER/CRZ therapy. In this work, a new UPLC-MS/MS method was developed and validated for the simultaneous determination of ALC, CER, and CRZ in rat plasma. Further application of the proposed method was performed to test the possibility of the PK interaction between bromelain and the selected ALK inhibitors in Wistar rats. Simple protein precipitation with acetonitrile was used for sample preparation. Chromatographic analysis was performed on Waters BEHTM C18 column with a mixture of acetonitrile/water containing 0.1% formic acid (70: 30, v/v) as the mobile phase. The method permitted the analysis of ALC, CER, and CRZ in concentration ranges of 2-200, 0.4-200, and 4.0-200 ng/mL, respectively. Bromelain administration caused a significant decrease in plasma levels of CER and CRZ with lowered Cmax, AUC0-t and AUC0-∞, along with an increase in the apparent clearance. However, no significant effect was noticed with ALC. Thus, attention should be paid to avoid the intake of bromelain with CER or CRZ.
Acid-reducing agents (ARAs) are the most commonly used medicines to treat patients with gastric acid-related disorders. ARA administration results in an elevation of intragastric pH and eases symptoms such as acid reflux. However, this effect could also lead to a reduction in the absorption of some co-administered oral medications (i.e. weakly basic drugs) by decreasing their gastric solubility. This in turn can result in a significant reduction of the efficacy of the co-administered oral medications. In order to address this problem, substantial efforts in translational modeling and the development of predictive in-vitro assays to better forecast the effect of ARA on oral absorption are conducted in the pharmaceutical industry. Despite these efforts, it remains challenging to predict the impact of ARAs on co-administered drugs. In this study, we evaluated the utility of Triskelion's Gastro-Intestinal Model (Tiny-TIM) in predicting ARA effect on twelve model drugs whose in-vivo data are available. The Tiny-TIM prediction of the ARA effect matched the observed effect of ARA co-administration in humans for the 12 model compounds. In summary, Tiny-TIM is a very reliable and promising GI model to successfully predict the nature of DDI when ARAs are co-administered with the drug of interest.
Renal (RIP) and hepatic (HIP) impairments are prevalent conditions in cancer patients. They can cause changes in gastric emptying time, albumin levels, hematocrit, glomerular filtration rate, hepatic functional volume, blood flow rates, and metabolic activity which can modify drug pharmacokinetics. Performing clinical studies in such populations has ethical and practical issues. Using predictive physiologically‐based pharmacokinetic (PBPK) models in the evaluation of the PK of alectinib, ruxolitinib, and panobinostat exposures in the presence of cancer, RIP, and HIP can help in using optimal doses with lower toxicity in these populations. Verified PBPK models were customized under scrutiny to account for the pathophysiological changes induced in these diseases. The PBPK model‐predicted plasma exposures in patients with different health conditions within 2‐average fold error. The PBPK model predicted an area under the curve ratio (AUCR) of 1, and 1.8, for ruxolitinib and panobinostat, respectively in the presence of severe RIP. On the other hand, the severe HIP was associated with AUCR of 1.4, 2.9, and 1.8 for alectinib, ruxolitinib, and panobinostat, respectively in agreement with the observed AUCR. Moreover, the PBPK model predicted that alectinib therapeutic cerebrospinal fluid levels are achieved in patients with non‐small cell lung cancer, moderate HIP, and severe HIP at 1, 1.5, and 1.8 fold that of healthy subjects. The customized PBPK models showed promising ethical alternatives for simulating clinical studies in patients with cancer, RIP, and HIP. More work is needed to quantify other pathophysiological changes induced by simultaneous affliction by cancer and RIP or HIP. This article is protected by copyright. All rights reserved.
During the past two decades, small-molecule kinase inhibitors have proven to be valuable in the treatment of solid and haematological tumours. However, because of their oral administration, the intrapatient and interpatient exposure to small-molecule kinase inhibitors (SMKIs) is highly variable and is affected by many factors, such as concomitant use of food and herbs. Food–drug interactions are capable of altering the systemic bioavailability and pharmacokinetics of these drugs. The most important mechanisms underlying food–drug interactions are gastrointestinal drug absorption and hepatic metabolism through cytochrome P450 isoenzymes. As food–drug interactions can lead to therapy failure or severe toxicity, knowledge of these interactions is essential. This Review provides a comprehensive overview of published studies involving food–drug interactions and herb–drug interactions for all registered SMKIs up to Oct 1, 2019. We critically discuss US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines concerning food-drug interactions and offer clear recommendations for their management in clinical practice.
Oncology drug development is among the most challenging of any therapeutic area, with first‐in‐human trials expected to deliver information on both safety and activity. Until recently, therapeutic approaches in oncology focused on cytotoxic chemotherapy agents, ruling out even the possibility of enrolling normal healthy volunteers (NHVs) in clinical trials due to safety considerations. The emergence of noncytotoxic modalities, including molecularly targeted agents with more favorable safety profiles, however, has led to increasing numbers of clinical pharmacology studies of these agents being conducted in NHVs. Beyond rapid enrollment and cost savings, there are other advantages of conducting specific types of studies in NHVs with the goal of more appropriate dosing decisions in certain subsets of the intended patient populations, allowing for enrollment of such patients in therapeutic trials from which they might otherwise have been excluded. Nevertheless, the decision must be carefully weighed against potential disadvantages, and although the considerations surrounding conduct of clinical trials using NHVs are generally well‐defined in most other therapeutic areas, they are less well‐defined in oncology.
Multikinase inhibitors (MKIs), including the tyrosine kinase inhibitors (TKIs), have rapidly become an established factor in daily (hemato)-oncology practice. Although the oral route of administration offers improved flexibility and convenience for the patient, challenges arise in the use of MKIs. As MKIs are prescribed extensively, patients are at increased risk for (severe) drug–drug interactions (DDIs). As a result of these DDIs, plasma pharmacokinetics of MKIs may vary significantly, thereby leading to high interpatient variability and subsequent risk for increased toxicity or a diminished therapeutic outcome. Most clinically relevant DDIs with MKIs concern altered absorption and metabolism. The absorption of MKIs may be decreased by concomitant use of gastric acid-suppressive agents (e.g. proton pump inhibitors) as many kinase inhibitors show pH-dependent solubility. In addition, DDIs concerning drug (uptake and efflux) transporters may be of significant clinical relevance during MKI therapy. Furthermore, since many MKIs are substrates for cytochrome P450 isoenzymes (CYPs), induction or inhibition with strong CYP inhibitors or inducers may lead to significant alterations in MKI exposure. In conclusion, DDIs are of major concern during MKI therapy and need to be monitored closely in clinical practice. Based on the current knowledge and available literature, practical recommendations for management of these DDIs in clinical practice are presented in this review.
Evaluation of the effect of food on the pharmacokinetics of oral oncology drugs is critical to drug development, as food can mitigate or exacerbate toxicities and alter systemic exposure. Our aim is to expand on current US Food and Drug Administration (FDA) guidance and provide data‐driven food‐effect study design recommendations specific to the oncology therapeutic area. Data for recently approved small‐molecule oncology drugs was extracted from the clinical pharmacology review in the sponsor's FDA submission package. Information on subject selection, meal types, timing of the study relative to the pivotal trial, and study outcomes was analyzed. The number of subjects enrolled ranged from 12 to 60, and the majority of studies (19 of 29) were conducted in healthy volunteers. Using AstraZeneca cost data, healthy volunteer studies were estimated to cost 10‐fold less than cancer patient studies. Nine of 29 (31%) studies included meals with multiple levels of fat content. Analysis of a subset of 16 drugs revealed that final results for the food‐effect study were available before the start of the pivotal trial for only 2 drugs. Conducting small food‐effect studies powered to estimate effect, rather than confirm no effect, with only a standardized high‐fat meal according to FDA guidance may eliminate unnecessary studies, reduce cost, and improve efficiency in oncology drug development. Starting food‐effect studies as early as possible is key to inform dosing in pivotal trials.
Alectinib (Alecensa®) is a potent and highly selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor. Oral alectinib monotherapy is approved in the EU as first-line treatment for adults with advanced ALK-positive non-small cell lung cancer (NSCLC) and for the treatment of adults with advanced ALK-positive NSCLC previously treated with crizotinib. In the USA, alectinib is indicated for the treatment of adults with ALK-positive metastatic NSCLC. The recommended dosage for alectinib in the EU and USA is 600 mg twice daily. Well-designed phase III studies in patients with ALK-positive NSCLC showed that during up to ≈ 19 months' follow-up, progression-free survival (PFS) was significantly improved with alectinib relative to crizotinib as first-line therapy (ALEX study), and relative to chemotherapy in patients previously treated with crizotinib and platinum-doublet chemotherapy (ALUR study). Central nervous system (CNS)-related outcomes were significantly improved with alectinib in both these settings. Two phase II registrational studies (NP28673 and NP28761) in patients previously treated with crizotinib also demonstrated the efficacy of alectinib, as assessed by objective response rates (ORRs), during up to 21 months' follow-up. Overall, alectinib had a manageable tolerability profile in these settings, with most adverse events (AEs) of mild or moderate severity. Current evidence indicates that alectinib is an important treatment option for patients with advanced ALK-positive NSCLC who are previously untreated or those previously treated with crizotinib. Given its efficacy and tolerability, current guidelines include alectinib as a treatment option in these settings, with the NCCN guidelines recommending it as a preferred option for first-line therapy.
The identification of anaplastic lymphoma kinase rearrangements in 2–5% of patients with non-small-cell lung cancer led to rapid advances in the clinical development of oral tyrosine kinase inhibitors. Anaplastic lymphoma kinase inhibitors are an effective treatment in preclinical models and patients with anaplastic lymphoma kinase-translocated cancers. Four anaplastic lymphoma kinase inhibitors (crizotinib, ceritinib, alectinib, and brigatinib) have recently been approved. Post-marketing studies provided additional pharmacokinetic information on their pharmacokinetic parameters. The pharmacokinetic properties of approved anaplastic lymphoma kinase inhibitors have been reviewed herein. Findings from additional studies on the effects of drug-metabolizing enzymes, drug transporters, and drug–drug interactions have been incorporated. Crizotinib, ceritinib, and alectinib reach their maximum plasma concentrations after approximately 6 h and brigatinib after 1–4 h. These drugs are primarily metabolized by cytochrome P450 3A with other cytochrome P450 enzymes. They are mainly excreted in the feces, with only a minor fraction being eliminated in urine. Crizotinib, ceritinib, and brigatinib are substrates for the adenosine triphosphate binding-cassette transporter B1, whereas alectinib is not. The different substrate specificities of the transporters play a key role in superior blood–brain barrier penetration by alectinib than by crizotinib and ceritinib. Although the absorption, distribution, and excretion of anaplastic lymphoma kinase inhibitors are regulated by drug transporters, their transporter-mediated pharmacokinetics have not yet been elucidated in detail in patients with non-small-cell lung cancer. Further research to analyze the contribution of drug transporters to the pharmacokinetics of anaplastic lymphoma kinase inhibitors in patients with non-small-cell lung cancer will be helpful for understanding the mechanisms of the inter-individual differences in the pharmacokinetics of anaplastic lymphoma kinase inhibitors.
Purpose
The labeling information, authorized by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), is expected to guide the method of drug administration with reference to meal intake, aiming at ensuring favorable safety profile and achieving optimal drug exposure. However, interactions between meals and a specific oral anticancer medication are complicated in that could be strongly affected by inter-individual variability in pharmacokinetics, meal compositions, and the timing of drug administration with respect to meal intake, which could lead to conflicting meal recommendations between regulatory authorities. The primary objective of this article was to systemically identify the conflicting food recommendations for oral antineoplastic drugs and explore the potential risks associated with these conflicting recommendations to patient-centered care.
Methods
We revisited, compared, and analyzed systemically the publicly accessible regulatory documents of the orally administered, anticancer drugs from the FDA and the EMA.
Results
After revisiting the labeling information and other regulatory documents of 43 oral oncology agents authorized by FDA during 2010–2016 and by the EMA at the time of this analysis finalized (December 2017), conflicting or inconsistent meal recommendations between the EMA and FDA were identified in 14% (6 of 43) oral anticancer drugs.
Conclusion
Conflicting food recommendations between regulatory authorities could have a large impact on anticancer treatment and patients’ quality of life, leading to suboptimal clinical outcomes. As the most important source of dosing instructions, the labeling information should be regularly recalibrated to provide consistent and informative instructions for drug intake in relation to meals, minimizing unintended interactions with meals and improving patient compliance and adherence. Further efforts on harmonizing food recommendations between regulatory agencies are highly warranted to assure optimal outcomes for individual patients. Moreover, meal-drug interaction studies should be conducted as early as possible to inform the dosing schedules of the subsequent phase 2 and phase 3 trials, thereby facilitating regulatory decision-making in regard to the method of drug administration.
The efficacy and safety of alectinib, a central nervous system-active and selective anaplastic lymphoma kinase (ALK) inhibitor, has been demonstrated in patients with ALK-positive (ALK+) non-small-cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time-dependent inhibition and small induction of CYP3A in vitro. We present results from three fixed-sequence studies evaluating drug–drug interactions for alectinib through CYP3A. Studies NP28990 and NP29042 enrolled 17 and 24 healthy subjects, respectively, and investigated potent CYP3A inhibition with posaconazole and potent CYP3A induction through rifampin, respectively, on the single oral dose pharmacokinetics (PK) of alectinib. A substudy of the global phase 2 NP28673 study enrolled 15 patients with ALK+ NSCLC to determine the effect of multiple doses of alectinib on the single oral dose PK of midazolam, a sensitive substrate of CYP3A. Potent CYP3A inhibition or induction resulted in only minor effects on the combined exposure of alectinib and M4. Multiple doses of alectinib did not influence midazolam exposure. These results suggest that dose adjustments may not be needed when alectinib is co-administered with CYP3A inhibitors or inducers, or for co-administered CYP3A substrates. This article is protected by copyright. All rights reserved
Anaplastic lymphoma kinase (ALK) inhibitor alectinib is an effective treatment for ALK-positive non-small-cell lung cancer. This bioequivalence study evaluated the in vivo performance of test 3 formulations with reduced wetting agent sodium lauryl sulphate (SLS) content. This randomized, 4-period, 4-sequence, crossover study compared alectinib (600 mg) as 25%, 12.5%, and 3% SLS hard capsule formulations with the reference 50% SLS clinical formulation in healthy subjects under fasted conditions (n = 49), and following a high-fat meal (n = 48). Geometric mean ratios and 90% confidence intervals (CIs) for Cmax, AUC0-last, and AUC0-∞, of alectinib, its major active metabolite, M4, and alectinib plus M4 were determined for the test formulations versus the reference formulation. Bioequivalence was concluded if the 90%CIs were within 80% to 125% boundaries. The 25% SLS formulation demonstrated bioequivalence to the reference 50% SLS formulation for Cmax, AUC0-last, and AUC0-∞ of alectinib, M4, and alectinib plus M4 under both fasted and fed conditions. Further reductions in SLS content (12.5% and 3% SLS) did not meet the bioequivalence criteria. Cross-group comparisons showed an ∼3-fold positive food effect. Reducing SLS to 25% resulted in a formulation that is bioequivalent to the current 50% SLS formulation used in alectinib pivotal trials. This article is protected by copyright. All rights reserved
1. Alectinib is a highly selective, central nervous system-active small molecule anaplastic lymphoma kinase inhibitor.
2. The absolute bioavailability, metabolism, excretion and pharmacokinetics of alectinib were studied in a two-period single-sequence crossover study. A 50 μg radiolabelled intravenous microdose of alectinib was co-administered with a single 600 mg oral dose of alectinib in the first period, and a single 600 mg/67 μCi oral dose of radiolabelled alectinib was administered in the second period to six healthy male subjects.
3. The absolute bioavailability of alectinib was moderate at 36.9%. Geometric mean clearance was 34.5 L/h, volume of distribution was 475 L and the hepatic extraction ratio was low (0.14).
4. Near-complete recovery of administered radioactivity was achieved within 168 h post-dose (98.2%) with excretion predominantly in faeces (97.8%) and negligible excretion in urine (0.456%). Alectinib and its major active metabolite, M4, were the main components in plasma, accounting for 76% of total plasma radioactivity. In faeces, 84% of dose was excreted as unchanged alectinib with metabolites M4, M1a/b and M6 contributing to 5.8%, 7.2% and 0.2% of dose, respectively.
5. This novel study design characterised the full absorption, distribution, metabolism and excretion properties in each subject, providing insight into alectinib absorption and disposition in humans.
Background:
ALK-rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK tyrosine kinase inhibitors (ALK inhibitors) such as crizotinib, but resistance invariably develops, often with progression in the brain. Ceritinib is a more potent ALK inhibitor than crizotinib in vitro, crosses the blood-brain barrier in vivo, and shows clinical responses in patients with crizotinib-resistant disease. We aimed to assess whole-body activity of ceritinib in both ALK inhibitor-pretreated and ALK inhibitor-naive patients with ALK-rearranged NSCLC.
Methods:
ASCEND-1 was an open-label, phase 1 trial that recruited patients from 20 academic hospitals or cancer centres in 11 countries in Europe, North America, and Asia-Pacific. Eligible patients were aged 18 years or older with ALK-rearranged locally advanced or metastatic cancer that had progressed despite standard therapy (or for which no effective standard therapy existed), who had at least one measurable lesion at baseline. The primary objective (to determine the maximum tolerated dose) has been reported previously. This updated analysis includes all patients with ALK-rearranged NSCLC given oral ceritinib at the recommended dose of 750 mg/day in the dose-escalation and expansion phases. Here we report the secondary outcomes of overall response, duration of response, and progression-free survival, analysed in all patients who received at least one 750 mg dose of ceritinib. Exploratory analyses included retrospective analysis of intracranial activity by independent neuroradiologists, in patients with untreated or locally treated neurologically stable brain metastases at baseline. Safety was assessed in all patients who received at least one dose of ceritinib. This study is no longer recruiting patients; however, treatment and follow-up are ongoing. This study is registered with ClinicalTrials.gov, number NCT01283516.
Findings:
Between Jan 24, 2011, and July 31, 2013, 255 patients were enrolled and received at least one dose of ceritinib 750 mg/day, of whom 246 had ALK-rearranged NSCLC. At data cutoff (April 14, 2014), median follow-up was 11·1 months (IQR 6·7-15·2) and 147 (60%) patients had discontinued treatment, 98 (40%) as a result of disease progression. An overall response was reported in 60 (72% [95% CI 61-82]) of 83 ALK inhibitor-naive patients and 92 (56% [49-64]) of 163 ALK inhibitor-pretreated patients. Median duration of response was 17·0 months (95% CI 11·3-non-estimable [NE]) in ALK inhibitor-naive patients and 8·3 months (6·8-9·7) in ALK inhibitor-pretreated patients. Median progression-free survival was 18·4 months (95% CI 11·1-NE) in ALK inhibitor-naive patients and 6·9 months (5·6-8·7) in ALK inhibitor-pretreated patients. Of 94 patients with retrospectively confirmed brain metastases and at least one post-baseline MRI or CT tumour assessment, intracranial disease control was reported in 15 (79% [95% CI 54-94]) of 19 ALK inhibitor-naive patients and in 49 (65% [54-76]) of 75 ALK inhibitor-pretreated patients. Of these 94 patients, 11 had measurable brain lesions and no previous radiotherapy to the brain, six of whom achieved a partial intracranial response. Serious adverse events were recorded in 117 (48%) of 246 patients. The most common grade 3-4 laboratory abnormalities were increased alanine aminotransferase (73 [30%] patients) and increased aspartate aminotransferase (25 [10%]). The most common grade 3-4 non-laboratory adverse events were diarrhoea and nausea, both of which occurred in 15 (6%) patients. Two on-treatment deaths during the study were deemed to be related to study drug by the investigators, one due to interstitial lung disease and one as a result of multiorgan failure that occurred in the context of infection and ischaemic hepatitis.
Interpretation:
The durable whole-body responses reported, together with the intracranial activity, support a clinical benefit for treatment with ceritinib in patients with ALK-rearranged NSCLC who have received crizotinib, or as an alternative to crizotinib. A confirmatory phase 2 clinical trial is ongoing to assess ceritinib activity in patients with ALK-rearranged NSCLC and brain or leptomeningeal metastases.
Funding:
Novartis Pharmaceuticals Corporation.
Background
Alectinib, a highly selective, central nervous system (CNS)-active anaplastic lymphoma kinase (ALK) inhibitor, demonstrated promising clinical activity in crizotinib-naïve and crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC). This phase 2 study evaluated the safety and efficacy of alectinib in ALK-positive NSCLC patients who progressed on previous crizotinib.
Methods
This ongoing North American study (NCT01871805) enrolled patients with stage IIIB/IV ALK-positive NSCLC, who had progressed following crizotinib. Patients were treated with oral alectinib 600 mg twice daily until progression, death or withdrawal. Primary endpoint was overall response rate (ORR) by independent review committee (IRC) using RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DOR), intracranial ORR and DOR, safety, and patient-reported outcomes. The intent-to-treat population was used for efficacy and safety analyses, with the response evaluable population used for response endpoints.
Findings
A total of 87 patients were enrolled in the intent-to-treat population. All patients had received prior crizotinib therapy, and 64 patients (74%) had also received prior chemotherapy. Fifty-two patients (60%) had baseline CNS metastases, of whom 18 (35%) had received no prior brain radiation therapy. At the time of primary analysis (median follow-up 4.8 months), ORR by IRC was 48% (95% CI 36–60). Adverse events were predominantly grade 1 or 2, most commonly constipation, fatigue, myalgia and peripheral edema. The most common grade ≥3 AEs were changes in laboratory values, including increased blood creatine phosphokinase (in 8%, n=7), increased alanine aminotransferase (in 6% n=5), and increased aspartate aminotransferase (in 5% n=4).
Interpretation
Alectinib demonstrated clinical efficacy and was well tolerated in patients with ALK-positive NSCLC who had progressed on crizotinib. Alectinib was active in the CNS, as demonstrated by durable responses in the majority of crizotinib-resistant patients with CNS disease. Therefore, alectinib could be a suitable treatment for patients with ALK-positive disease who have progressed on crizotinib.
Absorption of an orally administered drug with a pH-dependent solubility may be altered when it is co-administered with a gastric acid reducing agent (ARA). Assessing a drug's potential for pH-dependent drug-drug interactions (DDIs), considering study design elements for such DDI studies, interpreting and communicating study results in the drug labeling to guide drug dosing are important for drug development. We collected pertinent information from FDA approved new molecular entities (NMEs) containing clinical DDI studies with ARAs from January 2003 to May 2013. Based on assessments of the data of pH-solubility and in vivo DDI with ARAs, we proposed a conceptual framework for assessing the need for clinical pH-dependent DDI studies for weak base drugs (WBDs). Important study design considerations include selection of ARAs and timing of dosing of an ARA relative to the WBD in a DDI study. Labeling implications for drugs having DDIs with ARAs are also illustrated.Clinical Pharmacology & Therapeutics (2014); Accepted article preview online 14 April 2014; doi:10.1038/clpt.2014.87.
The identification of chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene in approximately 3-5% of non-small lung cancer (NSCLC) and the demonstration that the first-in-class ALK tyrosine kinase inhibitor, crizotinib, can effectively target these tumors represents a significant advance in the evolution of personalized medicine for NSCLC. Single arm studies demonstrating rapid and durable responses in the majority of ALK-positive NSCLC patients treated with crizotinib have been followed by a randomized phase 3 clinical trial where superiority of crizotinib over chemotherapy was seen in previously-treated ALK-positive NSCLC patients. However, despite the initial responses, most patients develop acquired resistance to crizotinib Several novel therapeutic approaches targeting ALK-positive NSCLC are currently under evaluation in clinical trials, including second-generation ALK inhibitors such as LDK378, CH5424802(RO5424802802), and AP26113, and HSP90 inhibitors.Clinical Pharmacology & Therapeutics (2013); Accepted article preview online 3 October 2013; doi:10.1038/clpt.2013.200.
Background:
In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown.
Methods:
We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival.
Results:
The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy.
Conclusions:
Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893.).
This article provides an unbiased review of the pharmacokinetic, pharmacodynamic, and drug-drug interaction data of telaprevir, an NS3/4A protease inhibitor. Telaprevir is well absorbed with fatty food, moderately protein bound (59-76 %) with a large volume of distribution (~252 L), primarily metabolized by cytochrome P450 (CYP) 3A4 and P-glycoprotein, and is largely excreted into feces. Pharmacokinetic and pharmacodynamic parameters are well described in healthy subjects and individuals infected with hepatitis C virus (HCV), although only limited data are available in specific patient subpopulations. Telaprevir is recommended to be given at 750 mg by mouth every 8 h for 12 weeks, in combination with peginterferon and ribavirin (the standard care). The addition of telaprevir to the standard care regimen results in increased sustained virological response in treatment-naïve patients (30 %) and treatment-experienced patients (up to 50 %), and works synergistically to lower viral resistance. Telaprevir is a substrate and/or inhibitor of CYP3A4 and P-glycoprotein, and drug-drug interaction studies in humans have focused on these pathways. Based on our analysis, a few reported drug-drug interactions may be classified as clinically significant, but more experiments under dosing conditions that resemble those given in the clinic are needed to understand the relevance of some of the reported interactions. Future studies should focus on the pharmacokinetics/pharmacodynamics of telaprevir in special populations or patients with concomitant conditions that will likely co-exist with HCV infection, with an emphasis on establishing pharmacokinetic-pharmacodynamic relationships. In vitro characterization of other phase 1-3 metabolic pathways could assist in elucidating the mechanisms of the drug-drug interactions observed in humans.
: Many patients with oncogene-driven non-small-cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors experience limited sites of disease progression. This study investigated retrospectively the benefits of local ablative therapy (LAT) to central nervous system (CNS) and/or limited systemic disease progression and continuation of crizotinib or erlotinib in patients with metastatic ALK gene rearrangement (ALK+) or EGFR-mutant (EGFR-MT) NSCLC, respectively.
: Patients with metastatic ALK+ NSCLC treated with crizotinib (n = 38) and EGFR-MT NSCLC treated with erlotinib (n = 27) were identified at a single institution. Initial response to the respective kinase inhibitors, median progression-free survival (PFS1), and site of first progression were recorded. A subset of patients with either nonleptomeningeal CNS and/or four sites or fewer of extra-CNS progression (oligoprogressive disease) suitable for LAT received either radiation or surgery to these sites and continued on the same tyrosine kinase inhibitors. The subsequent median progression-free survival from the time of first progression (PFS2) and pattern of progression were recorded.
: Median progression-free survival in ALK+ patients on crizotinib was 9.0 months, and 13.8 months for EGFR-MT patients on erlotinib. Twenty-five of 51 patients (49%) who progressed were deemed suitable for local therapy (15 ALK+, 10 EGFR-MT; 24 with radiotherapy, one with surgery) and continuation of the same targeted therapy. Post-LAT, 19 of 25 patients progressed again, with median PFS2 of 6.2 months.
: Oncogene-addicted NSCLC with CNS and/or limited systemic disease progression (oligoprogressive disease) on relevant targeted therapies is often suitable for LAT and continuation of the targeted agent, and is associated with more than 6 months of additional disease control.
Most anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancers (NSCLCs) are highly responsive to treatment with ALK tyrosine kinase inhibitors (TKIs). However, patients with these cancers invariably relapse, typically within 1 year, because of the development of drug resistance. Herein, we report findings from a series of lung cancer patients (n = 18) with acquired resistance to the ALK TKI crizotinib. In about one-fourth of patients, we identified a diverse array of secondary mutations distributed throughout the ALK TK domain, including new resistance mutations located in the solvent-exposed region of the adenosine triphosphate-binding pocket, as well as amplification of the ALK fusion gene. Next-generation ALK inhibitors, developed to overcome crizotinib resistance, had differing potencies against specific resistance mutations. In addition to secondary ALK mutations and ALK gene amplification, we also identified aberrant activation of other kinases including marked amplification of KIT and increased autophosphorylation of epidermal growth factor receptor in drug-resistant tumors from patients. In a subset of patients, we found evidence of multiple resistance mechanisms developing simultaneously. These results highlight the unique features of TKI resistance in ALK-positive NSCLCs and provide the rationale for pursuing combinatorial therapeutics that are tailored to the precise resistance mechanisms identified in patients who relapse on crizotinib treatment.
Patients with anaplastic lymphoma kinase (ALK) gene rearrangements often manifest dramatic responses to crizotinib, a small-molecule ALK inhibitor. Unfortunately, not every patient responds and acquired drug resistance inevitably develops in those who do respond. This study aimed to define molecular mechanisms of resistance to crizotinib in patients with ALK(+) non-small cell lung cancer (NSCLC).
We analyzed tissue obtained from 14 patients with ALK(+) NSCLC showing evidence of radiologic progression while on crizotinib to define mechanisms of intrinsic and acquired resistance to crizotinib.
Eleven patients had material evaluable for molecular analysis. Four patients (36%) developed secondary mutations in the tyrosine kinase domain of ALK. A novel mutation in the ALK domain, encoding a G1269A amino acid substitution that confers resistance to crizotinib in vitro, was identified in two of these cases. Two patients, one with a resistance mutation, exhibited new onset ALK copy number gain (CNG). One patient showed outgrowth of epidermal growth factor receptor (EGFR) mutant NSCLC without evidence of a persistent ALK gene rearrangement. Two patients exhibited a KRAS mutation, one of which occurred without evidence of a persisting ALK gene rearrangement. One patient showed the emergence of an ALK gene fusion-negative tumor compared with the baseline sample but with no identifiable alternate driver. Two patients retained ALK positivity with no identifiable resistance mechanism.
Crizotinib resistance in ALK(+) NSCLC occurs through somatic kinase domain mutations, ALK gene fusion CNG, and emergence of separate oncogenic drivers.
The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion oncogene represents a molecular target in a small subset of non-small cell lung cancers (NSCLCs). This fusion leads to constitutive ALK activation with potent transforming activity. In a pivotal phase 1 clinical trial, the ALK tyrosine kinase inhibitor (TKI) crizotinib (PF-02341066) demonstrated impressive antitumor activity in the majority of patients with NSCLC harboring ALK fusions. However, despite these remarkable initial responses, cancers eventually develop resistance to crizotinib, usually within 1 y, thereby limiting the potential clinical benefit. To determine how cancers acquire resistance to ALK inhibitors, we established a model of acquired resistance to crizotinib by exposing a highly sensitive EML4-ALK-positive NSCLC cell line to increasing doses of crizotinib until resistance emerged. We found that cells resistant to intermediate doses of crizotinib developed amplification of the EML4-ALK gene. Cells resistant to higher doses (1 μM) also developed a gatekeeper mutation, L1196M, within the kinase domain, rendering EML4-ALK insensitive to crizotinib. This gatekeeper mutation was readily detected using a unique and highly sensitive allele-specific PCR assay. Although crizotinib was ineffectual against EML4-ALK harboring the gatekeeper mutation, we observed that two structurally different ALK inhibitors, NVP-TAE684 and AP26113, were highly active against the resistant cancer cells in vitro and in vivo. Furthermore, these resistant cells remained highly sensitive to the Hsp90 inhibitor 17-AAG. Thus, we have developed a model of acquired resistance to ALK inhibitors and have shown that second-generation ALK TKIs or Hsp90 inhibitors are effective in treating crizotinib-resistant tumors harboring secondary gatekeeper mutations.
Several decades of cancer research have revealed a pivotal role for tyrosine kinases as key regulators of signaling pathways, controlling cell growth and differentiation. Deregulation of tyrosine kinase-mediated signaling occurs frequently in cancer and is believed to drive the initiation and progression of disease. Chromosomal rearrangements involving the tyrosine kinase anaplastic lymphoma kinase (ALK) occur in a variety of human malignancies including non-small cell lung cancer (NSCLC), anaplastic large cell lymphomas, and inflammatory myofibroblastic tumors. The aberrant activation of ALK signaling leads to "oncogene addiction" and marked sensitivity to ALK inhibitors such as crizotinib (PF-02341066). This review focuses on ALK rearrangements in NSCLC, starting with the discovery of the EML4-ALK fusion oncogene, and culminating in the recent validation of ALK as a therapeutic target in patients with ALK-rearranged NSCLC. Current efforts seek to expand the role of ALK kinase inhibition in lung and other cancers and to address the molecular basis for the development of resistance.
Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase.
After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy.
Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects.
The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).
7053
Background: Nilotinib, a highly selective and potent BCR-ABL tyrosine kinase inhibitor, is approved for the treatment of CML-CP and CML-AP patients resistant or intolerant to prior therapy including imatinib. The solubility of nilotinib is pH dependent, with lower solubility at higher pH. We evaluated whether esomeprazole, a potent proton pump inhibitor (PPI) that can significantly increase gastric pH, could affect the oral absorption and pharmacokinetics of nilotinib in healthy subjects. Methods: Twenty-two subjects (6 F, 16M, age range 18–64 years) were enrolled to receive nilotinib alone or in the presence of steady-state esomeprazole during two treatment periods. Nilotinib was given as a single oral 400 mg dose on days 1 and 13, and esomeprazole 40 mg once-daily on day 8 through day 13. Serial blood samples were collected up to 72 hours after nilotinib dosing for determination of nilotinib serum concentrations by a validated liquid chromatography-tandem mass spectrometry assay. Gastric pH was monitored in all subjects at baseline (prior to nilotinib and esomeprazole dosing), before and during the first 4 hrs of esomeprazole steady state dosing (fifth dose on Day 12). Results: When coadministered with esomeprazole, nilotinib C max was decreased by 27% (397±89 vs 303±157ng/mL) and AUC 0-∞ decreased by 34% (11515±6140 vs 7164±3752ng*hr/mL) respectively. The median time to reach nilotinib C max was slightly prolonged from 4.0 hrs to 6.0 hrs, but its elimination half-life was not altered (17.3±10.7 vs 15.9±6.6 hrs). Median gastric pH was increased from 0.8 at baseline to 2.0 at pre-dose, and to 3.9, 5.8, 5.5, and 5.7 at 1, 2, 3, and 4 hrs after esomeprazole dosing. Administration of nilotinib alone or in combination with esomeprazole was generally well tolerated in the study subjects. Conclusions: The study results demonstrate a modest reduction in the rate and extent of nilotinib absorption when co-administered with esomeprazole. Such an effect is unlikely to cause a significant clinical consequence for nilotinib therapy, and thus nilotinib can be used with esomeprazole or other PPIs without the risk of substantial decrease in nilotinib systemic exposure.
[Table: see text]
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Background: Crizotinib is a first-in-class oral ALK inhibitor for the treatment (tx) of advanced ALK-positive (ALK+) NSCLC. Dramatic and prolonged responses to crizotinib are common, but pts do experience PD. Methods: Clinical characteristics of ALK+ NSCLC pts enrolled onto two multicenter, single arm trials of crizotinib (A8081001, PROFILE 1005) with investigator-defined PD who were allowed to continue crizotinib if, in the investigator’s opinion, there was reasonable evidence of ongoing clinical benefit were assessed. A period of ≥2 wks was chosen as a reasonable minimum duration of post-PD crizotinib tx. Results: As of 1 June 2011, 146 pts (A8081001, n=61, PROFILE 1005, n=85) had PD. PD was observed in new lesions only (1 organ site, n=62; >1 organ site, n=18), target ± new lesions (≥ 1 organ site, n=55), clinical PD (n=9), and no site assessment (n=2). Most common new lesions in single organ sites were brain (brain MRI not mandatory; n=25), liver (n=20), bone (n=4), and kidney (n=1). Of the 146 pts, 78 (53%) received crizotinib post-PD for at least 2 wks, 91% of whom had ECOG PS 0 or 1 at PD. In these 78 pts, PD was observed in new lesions only (1 organ site, n=39; >1 organ site, n=4), target ± new lesions (≥ 1 organ site, n=29), and clinical PD (n=6); the most common sites for single organ PD were brain (n=20), liver (n=9), and other (n=10). Best response before PD (% CR/PR, SD, PD) was 62/27/12 in the 78 pts who received ≥2 weeks’ tx post-PD and 31/37/32 in the 68 pts who received <2 weeks’ tx post-PD or discontinued. Median duration of crizotinib tx post-PD (n=78) was 10 weeks (range 2–84). 20 pts with PD in brain only (concurrent local tx or radiation permitted) continue to receive crizotinib (range 3–82 weeks post-PD). Conclusions: Following initial crizotinib tx, PD most commonly occurred at a single organ site in ALK+ NSCLC pts. The majority of pts receiving crizotinib post-PD had good PS, and tended to have single-site PD (most often the brain or liver), and a prior response on crizotinib. Given these observations, pts may be able to continue with crizotinib for a period of time following clinical or documented progression.
The efficacy and safety of alectinib, a central nervous system-active and selective anaplastic lymphoma kinase (ALK) inhibitor, has been demonstrated in patients with ALK-positive (ALK+) non-small-cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time-dependent inhibition and small induction of CYP3A in vitro. We present results from three fixed-sequence studies evaluating drug–drug interactions for alectinib through CYP3A. Studies NP28990 and NP29042 enrolled 17 and 24 healthy subjects, respectively, and investigated potent CYP3A inhibition with posaconazole and potent CYP3A induction through rifampin, respectively, on the single oral dose pharmacokinetics (PK) of alectinib. A substudy of the global phase 2 NP28673 study enrolled 15 patients with ALK+ NSCLC to determine the effect of multiple doses of alectinib on the single oral dose PK of midazolam, a sensitive substrate of CYP3A. Potent CYP3A inhibition or induction resulted in only minor effects on the combined exposure of alectinib and M4. Multiple doses of alectinib did not influence midazolam exposure. These results suggest that dose adjustments may not be needed when alectinib is co-administered with CYP3A inhibitors or inducers, or for co-administered CYP3A substrates. This article is protected by copyright. All rights reserved
Alectinib, a lipophilic, basic, anaplastic lymphoma kinase (ALK) inhibitor with very low aqueous solubility, has received Food and Drug Administration-accelerated approval for the treatment of patients with ALK+ non-small-cell lung cancer. This paper describes the application of physiologically based absorption modeling during clinical development to predict and understand the impact of food and gastric pH changes on alectinib absorption. The GastroPlus™ software was used to develop an absorption model integrating in vitro and in silico data on drug substance properties. Oral pharmacokinetics was simulated by linking the absorption model to a disposition model fit to pharmacokinetic data obtained after an intravenous infusion. Simulations were compared to clinical data from a food effect study and a drug-drug interaction study with esomeprazole, a gastric acid-reducing agent. Prospective predictions of a positive food effect and negligible impact of gastric pH elevation were confirmed with clinical data, although the exact magnitude of the food effect could not be predicted with confidence. After optimization of the absorption model with clinical food effect data, a refined model was further applied to derive recommendations on the timing of dose administration with respect to a meal. The application of biopharmaceutical absorption modeling is an area with great potential to further streamline late stage drug development and with impact on regulatory questions.
Background:
Alectinib is a novel anaplastic lymphoma kinase (ALK) inhibitor for treatment of patients with ALK-positive non-small-cell lung cancer who have progressed on or are intolerant to crizotinib. To support clinical development, concentrations of alectinib and metabolite M4 were determined in plasma from patients and healthy subjects.
Methods:
LC-MS/MS methods were developed and validated in two different laboratories: Chugai used separate assays for alectinib and M4 in a pivotal Phase I/II study while Roche established a simultaneous assay for both analytes for another pivotal study and all other studies.
Conclusion:
Cross-validation assessment revealed a bias between the two bioanalytical laboratories, which was confirmed with the clinical PK data between both pivotal studies using the different bioanalytical methods.
1. Alectinib is a highly selective, central nervous system-active small molecule anaplastic lymphoma kinase inhibitor.
2. The absolute bioavailability, metabolism, excretion and pharmacokinetics of alectinib were studied in a two-period single-sequence crossover study. A 50 μg radiolabelled intravenous microdose of alectinib was co-administered with a single 600 mg oral dose of alectinib in the first period, and a single 600 mg/67 μCi oral dose of radiolabelled alectinib was administered in the second period to six healthy male subjects.
3. The absolute bioavailability of alectinib was moderate at 36.9%. Geometric mean clearance was 34.5 L/h, volume of distribution was 475 L and the hepatic extraction ratio was low (0.14).
4. Near-complete recovery of administered radioactivity was achieved within 168 h post-dose (98.2%) with excretion predominantly in faeces (97.8%) and negligible excretion in urine (0.456%). Alectinib and its major active metabolite, M4, were the main components in plasma, accounting for 76% of total plasma radioactivity. In faeces, 84% of dose was excreted as unchanged alectinib with metabolites M4, M1a/b and M6 contributing to 5.8%, 7.2% and 0.2% of dose, respectively.
5. This novel study design characterised the full absorption, distribution, metabolism and excretion properties in each subject, providing insight into alectinib absorption and disposition in humans.
Purpose:
Crizotinib confers improved progression-free survival compared with chemotherapy in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC), but progression invariably occurs. We investigated the efficacy and safety of alectinib, a potent and selective ALK inhibitor with excellent CNS penetration, in patients with crizotinib-refractory ALK-positive NSCLC.
Patients and methods:
Alectinib 600 mg was administered orally twice daily. The primary end point was objective response rate (ORR) by central independent review committee (IRC).
Results:
Of the 138 patients treated, 84 patients (61%) had CNS metastases at baseline, and 122 were response evaluable (RE) by IRC. ORR by IRC was 50% (95% CI, 41% to 59%), and the median duration of response (DOR) was 11.2 months (95% CI, 9.6 months to not reached). In 96 patients (79%) previously treated with chemotherapy, the ORR was 45% (95% CI, 35% to 55%). Median IRC-assessed progression-free survival for all 138 patients was 8.9 months (95% CI, 5.6 to 11.3 months). CNS disease control rate was 83% (95% CI, 74% to 91%), and the median CNS DOR was 10.3 months (95% CI, 7.6 to 11.2 months). CNS ORR in 35 patients with baseline measurable CNS lesions was 57% (95% CI, 39% to 74%). Of the 23 patients with baseline CNS metastases (measurable or nonmeasurable) and no prior radiation, 10 (43%) had a complete CNS response. At 12 months, the cumulative CNS progression rate (24.8%) was lower than the cumulative non-CNS progression rate (33.2%) for all patients. Common adverse events were constipation (33%), fatigue (26%), and peripheral edema (25%); most were grade 1 to 2.
Conclusion:
Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALK-positive NSCLC, including those with CNS metastases.
Ceritinib is a potent inhibitor of anaplastic lymphoma kinase (ALK), which has shown acceptable safety and substantial antitumor activity in ALK-positive non-small cell lung cancer (NSCLC) patients. Two food-effect studies were conducted in healthy adults to investigate the influence of food on the oral bioavailability of ceritinib: a study with low- or high-fat meals at 500 mg, and a study with a light snack at 750 mg. Compared with the fasted state, AUC0-∞ (90% CI) of ceritinib was increased by 58% (34%, 86%) after the intake of a low-fat meal, by 73% (46%, 105%) after the intake of a high-fat meal, and by 54% (19%, 99%) after the intake of a light snack. Safety assessments also suggested that food may improve gastrointestinal (GI) tolerability after a single ceritinib dose. Based on the pharmacokinetic results, it is essential to avoid any type of meal during dosing of ceritinib as the intake of food may increase the occurrence of exposure-dependent, non-GI toxicities at the labeled dose of 750 mg daily during fasting. A randomized trial is ongoing to determine an alternative way to give ceritinib (450 mg or 600 mg with food) that may enhance GI tolerability in ALK-positive NSCLC patients. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
ALK fusion oncogenes represent a novel molecular target in a small subset of non-small cell lung cancers (NSCLC). The vast majority of patients with ALK-positive NSCLC are highly responsive to ALK tyrosine kinase inhibitor (TKI) therapy. However, these patients invariably relapse, typically within one year, due to the development of resistance. Herein, we report findings from the first series of patients with acquired resistance to the ALK TKI crizotinib. In approximately one-third of patients, we identified a diverse array of secondary mutations distributed throughout the ALK TK domain. We also identified aberrant activation of other kinases as alternative mechanisms of crizotinib resistance. Additionally, we generated laboratory models of acquired crizotinib resistance which closely recapitulate the diversity of resistance mechanisms observed in patients. Our results highlight the marked heterogeneity of TKI resistance mechanisms in ALK-positive NSCLC, and provide the rationale for pursuing combinatorial therapeutic strategies in patients who relapse on crizotinib.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5593. doi:1538-7445.AM2012-5593
Cabozantinib is a small molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. Cabozantinib exhibits a pH-dependent solubility profile in vitro. Two phase 1 clinical pharmacology studies were conducted in healthy subjects to evaluate whether factors that may affect cabozantinib solubility and gastric pH could alter cabozantinib bioavailability: a food effect study (Study 1), and a drug-drug interaction (DDI) study with proton pump inhibitor (PPI) esomeprazole (Study 2). Following a high-fat meal (Study 1), cabozantinib Cmax and AUCs were increased (40.5% and 57%, respectively) and the median tmax was delayed by 2 hours. Cabozantinib should thus not be taken with food (patients should not eat for at least 2 hours before and at least 1 hour after administration). In the DDI study (Study 2), the 90% confidence intervals (CIs) around the ratio of least-squares means of cabozantinib with esomeprazole versus cabozantinib alone for AUC0-inf were within the 80 - 125% limits; the upper 90% CI for Cmax was 125.1%. Due to the low apparent risk of a DDI, concomitant use of PPIs or weaker gastric pH altering agents with cabozantinib is not contraindicated. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
On April 29, 2014, the FDA granted accelerated approval to ceritinib (ZYKADIA™, Novartis Pharmaceuticals Corporation), a breakthrough therapy-designated drug, for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. The approval was based on a single-arm multicenter trial enrolling 163 patients with metastatic ALK-positive NSCLC who had disease progression on (91%) or intolerance to crizotinib. Patients received ceritinib at a starting dose of 750 mg orally once daily. The objective response rate (ORR) by a blinded independent review committee (BIRC) was 44% (95% CI, 36-52), and the median duration of response (DOR) was 7.1 months. The ORR by investigator assessment was similar. Safety was evaluated in 255 patients. The most common adverse reactions (ARs) and laboratory abnormalities included diarrhea (86%), nausea (80%), increased alanine transaminase (80%), increased aspartate transaminase (75%), vomiting (60%), increased glucose (49%), and increased lipase (28%). Although 74% of patients required at least one dose reduction or interruption due to ARs, the discontinuation rate due to ARs was low (10%). With this safety profile, the benefit-risk analysis was considered favorable because of the clinically meaningful ORR and DOR.
Copyright © 2015, American Association for Cancer Research.
The aim of this study was to evaluate the effect of coadministration of acid-reducing agents on the pharmacokinetic exposure of orally administered epidermal growth factor receptor inhibitor erlotinib, a drug that displays pH-dependent solubility. Two studies were conducted, the first with the proton pump inhibitor omeprazole and the second with the H2-receptor antagonist ranitidine. Twenty-four healthy male and female volunteers were enrolled in each study. Erlotinib was administered as a single oral 150 mg dose on day 1. After the washout a subsequent study period evaluated 150 mg erlotinib administered with the acid-reducing agent. Omeprazole (40 mg once daily) was given on days 11-14, concomitantly with erlotinib on day 15, and for two additional days (days 16-17). In the ranitidine study, on day 13, participants were randomized to either concomitant dosing (treatment B) or staggered administration (treatment C) of erlotinib and ranitidine and crossed over to the other treatment starting on day 27. For treatment B, ranitidine (300 mg once daily) was administered in the morning for 5 days, 2 h before erlotinib. For treatment C, ranitidine was administered as a divided dose (150 mg twice daily) for 5 days, with erlotinib given 10 h after the previous evening dose and 2 h before the next ranitidine morning dose. Plasma samples were obtained for determination of the concentrations of erlotinib and its metabolite OSI-420, following each erlotinib dose. All participants were monitored for safety and tolerability. The geometric mean ratios of AUC0-∞ and Cmax for erlotinib and AUC0-last and Cmax for OSI-420 were substantially decreased when erlotinib was dosed with omeprazole. The estimated mean ratio (90% confidence interval) for erlotinib was 0.54 (0.49-0.59) for AUC0-∞ and 0.39 (0.32-0.48) for Cmax. For OSI-420, the estimated mean ratio was 0.42 (0.37-0.48) for AUC0-last and 0.31 (0.24-0.41) for Cmax. AUC0-∞ and Cmax for erlotinib were substantially decreased by 33 and 54%, respectively, upon coadministration with ranitidine, but the decrease was only 15 and 17% when ranitidine and erlotinib were given staggered. Similar results were observed for the metabolite OSI-420. Erlotinib was generally well-tolerated alone or in combination with omeprazole or ranitidine. Erlotinib pharmacokinetic exposure was substantially reduced upon coadministration with omeprazole and ranitidine, but not when administered with a staggered dosing approach to ranitidine. Therefore, it is recommended that the concomitant use of erlotinib with proton pump inhibitors be avoided. If treatment with an H2-receptor antagonist such as ranitidine is required, erlotinib must be administered 10 h after the H2-receptor antagonist dosing and at least 2 h before the next dose of the H2-receptor antagonist.
Crizotinib is an oral kinase inhibitor approved for the treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). The clinical benefits of crizotinib in patients with brain metastases have not been previously studied.
Patients with advanced ALK-rearranged NSCLC enrolled onto clinical trial PROFILE 1005 or 1007 (randomly assigned to crizotinib) were included in this retrospective analysis. Patients with asymptomatic brain metastases (nontarget or target lesions) were allowed to enroll. Tumor assessments were evaluated every 6 weeks using RECIST (version 1.1).
At baseline, 31% of patients (275 of 888) had asymptomatic brain metastases; 109 had received no prior and 166 had received prior brain radiotherapy as treatment. Among patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR) at 12 weeks was 63% (95% CI, 54% to 72%), the intracranial DCR was 56% (95% CI, 46% to 66%), and the median intracranial time to progression (TTP) was 7 months (95% CI, 6.7 to 16.4). Among patients with previously treated brain metastases, the systemic DCR was 65% (95% CI, 57% to 72%), the intracranial DCR was 62% (95% CI, 54% to 70%), and the median intracranial TTP was 13.2 months (95% CI, 9.9 to not reached). Patients with systemic disease control were also likely to experience intracranial disease control at 12 weeks (correlation coefficient, 0.7652; P < .001). Among patients without baseline brain metastases who developed progressive disease (n = 253) after initiation of crizotinib, 20% were diagnosed with brain metastases.
Crizotinib was associated with systemic and intracranial disease control in patients with ALK-rearranged NSCLC who were ALK inhibitor naive and had brain metastases. However, progression of preexisting or development of new intracranial lesions while receiving therapy was a common manifestation of acquired resistance to crizotinib.
© 2015 by American Society of Clinical Oncology.
The treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small molecule inhibitor of the tyrosine kinases ALK, ROS1, and MET. Resistance to crizotinib invariably develops, however, through a variety of mechanisms. In the last few years, a flurry of new and more potent ALK inhibitors has emerged for the treatment of ALK-positive NSCLC, including ceritinib (LDK378), alectinib (RO5424802/CH5424802), AP26113, ASP3026, TSR-011, PF-06463922, RXDX-101, X-396, and CEP-37440. Cancers harboring ALK rearrangements may also be susceptible to treatment with heat shock protein 90 inhibitors. This review focuses on the pharmacologic and clinical properties of these compounds, either as monotherapies or in combination with other drugs. With so many ALK inhibitors in development, the challenges of how these agents should be studied and ultimately prescribed are also discussed.
Purpose:
The clinical efficacy of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib has been demonstrated in ALK fusion-positive non-small cell lung cancer (NSCLC); however, brain metastases are frequent sites of initial failure in patients due to poor penetration of the central nervous system by crizotinib. Here, we examined the efficacy of a selective ALK inhibitor alectinib/CH5424802 in preclinical models of intracranial tumors.
Methods:
We established intracranial tumor implantation mouse models of EML4-ALK-positive NSCLC NCI-H2228 and examined the antitumor activity of alectinib in this model. Plasma distribution and brain distribution of alectinib were examined by quantitative whole-body autoradiography administrating a single oral dose of (14)C-labeled alectinib to rats. The drug permeability of alectinib was evaluated in Caco-2 cell.
Results:
Alectinib resulted in regression of NCI-H2228 tumor in mouse brain and provided a survival benefit. In a pharmacokinetic study using rats, alectinib showed a high brain-to-plasma ratio, and in an in vitro drug permeability study using Caco-2 cells, alectinib was not transported by P-glycoprotein efflux transporter that is a key factor in blood-brain barrier penetration.
Conclusions:
We established intracranial tumor implantation models of EML4-ALK-positive NSCLC. Alectinib showed potent efficacy against intracranial EML4-ALK-positive tumor. These results demonstrated that alectinib might provide therapeutic opportunities for crizotinib-treated patients with brain metastases.
Background
Erlotinib is a key therapy for advanced non-small cell lung cancer (NSCLC). Concurrent acid suppression (AS) therapy with tyrosine kinase inhibitors (TKIs) may reduce TKI plasma levels. Given gastroesophageal reflux disease prevalence, this retrospective analysis was undertaken to determine if co-administering erlotinib with AS affected NSCLC outcomes.
Patients and Methods
Advanced NSCLC patients receiving erlotinib from 2007-2012 at a large, centralized, cancer institution were retrospectively reviewed. Pertinent demographics were collected and concomitant AS treatment was defined as AS prescription dates overlapping with ≥ 20% of erlotinib treatment duration. Patients who received erlotinib for ≥ 1 week were analyzed for progression free survival (PFS) and overall survival (OS).
Results
Stage IIIB/IV NSCLC patients (n=544) were identified and 507 had adequate data for review. Median age was 64 years and 272 were female. Adenocarcinoma (318, 64%) and squamous (106, 21%) were predominant subtypes; 124 patients received concomitant AS. In this unselected population, median PFS and OS in AS vs. non-AS groups were 1.4 vs. 2.3 months (p<0.001) and 12.9 vs. 16.8 months (p=0.003), respectively. Factoring gender, subtype, and performance status in multivariate Cox proportional hazards ratios for PFS and OS between AS and non-AS groups were 1.83 (95% CI 1.48-2.25) and 1.37 (95% CI 1.11-1.69) respectively.
Conclusion
This large population-based study suggests erlotinib efficacy may be linked with gastric pH and OS could be adversely affected. This is the first study demonstrating a possible negative clinical impact of co-administering erlotinib with AS therapy. Further prospective investigation is warranted.
Ceritinib is an oral anaplastic lymphoma kinase (ALK) inhibitor developed by Novartis for the treatment of tumours characterised by genetic abnormalities in ALK. ALK is a member of the insulin receptor family of tyrosine kinases that can become oncogenic when fused to other proteins. Ceritinib has been approved in the US under 'Breakthrough Therapy' designation for the second-line treatment of ALK-positive non-small cell lung cancer (NSCLC). Regulatory submissions have also been made in the EU and other countries. Phase III development is ongoing worldwide to evaluate ceritinib both as a first- and second-line therapy for ALK-positive NSCLC. This article summarizes the milestones in the development of ceritinib leading to this first approval for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib.
The clinical efficacy of the ALK inhibitor crizotinib has been demonstrated in ALK fusion-positive NSCLC; however, resistance to crizotinib certainly occurs through ALK secondary mutations in clinical use. Here we examined the efficacy of a selective ALK inhibitor alectinib/CH5424802 in models of crizotinib resistance. Alectinib led to tumor size reduction in EML4-ALK-positive xenograft tumors that failed to regress fully during the treatment with crizotinib. In addition, alectinib inhibited the growth of some EML4-ALK mutant-driven tumors, including the G1269A model. These results demonstrated that alectinib might provide therapeutic opportunities for crizotinib-treated patients with ALK secondary mutations.
Introduction:
Boceprevir is an NS3/NS4A serine protease inhibitor that was approved for use in Hepatitis C virus (HCV) genotype 1 patients by the US Food and Drug Administration (FDA) in May 2011. The approval of this protease inhibitor marked a major paradigm shift in the treatment of HCV, as it was one of the first of many new small molecules specifically designed and approved for HCV.
Areas covered:
In this article, the authors summarize boceprevir's pharmacokinetic and pharmacodynamic properties. In addition, they review Phase II and III trials of boceprevir as well as its clinical efficacy, dosing and safety.
Expert opinion:
Boceprevir is a potent protease inhibitor for the treatment of genotype 1 HCV. It has a well-tolerated side-effect profile and increases the likelihood of SVR in naïve and previously treated patients. The impending release of newer more efficacious direct-acting antivirals may limit the use of boceprevir for patients infected with HCV.
Acid-reducing agents (ARAs) are the most commonly prescribed medications in North America and Western Europe. There are currently no data describing the prevalence of their use among cancer patients. However, this is a paramount question due to the potential for significant drug-drug interactions (DDI) between ARAs, most commonly proton-pump-inhibitors (PPIs), and orally administered cancer therapeutics that display pH-dependent solubility, which may lead to decreased drug absorption and decreased therapeutic-benefit. Of recently approved orally administered cancer therapeutics, >50% are characterized as having pH-dependent solubility but there are currently no data describing the prevalence of the potential ARA-DDI liability among targeted agents currently in clinical development. The objectives of this study were to 1) determine the prevalence of ARA use among different cancer populations and 2) investigate the prevalence of orally administered cancer therapeutics currently in development that may be liable for an ARA-DDI. To address the question of ARA use among cancer patients, a retrospective cross-sectional analysis was performed using two large healthcare databases - Thomson Reuters MarketScan (N=1,776,443) and Veterans Affairs (VA, N=1,171,833). Among all cancer patients, the total prevalence proportion of ARA use (# cancer patients receiving an ARA/total # cancer patients) was 20% and 33% for the MarketScan and VA databases, respectively. PPIs were the most commonly prescribed agent, comprising 79% and 65% of all cancer patients receiving a prescription for an ARA (# cancer patients receiving a PPI /# cancer patients receiving an ARA) for the MarketScan and VA databases, respectively. To estimate the ARA-DDI liability of orally-administered molecular targeted cancer therapeutics currently in development, two publicly available databases - 1) Kinase SARfari and 2) canSAR - were examined. For those orally administered clinical candidates that had available structures, the pka's and corresponding relative solubilities were calculated for a normal fasting pH of 1.2 and an "ARA-hypochlorhydric" pH of 4. Taking calculated pka's and relative solubilities into consideration, clinical candidates were classified based on their risk for an ARA-DDI. Nearly one-third (29%) of the molecules investigated are at high risk for an ARA-DDI, and of those high risk molecules, two-thirds (67%) are being clinically evaluated for at least one of five cancer types with the highest prevalence of ARA use (gastrointestinal, pancreatic, lung, glioblastoma multiforme, GIST). These data strongly suggest that, with the clinical development of ARA-DDI-susceptible cancer therapeutics, will come continued challenges for drug-development scientists, oncologists and regulatory agencies in ensuring that patients achieve safe and efficacious exposures of their cancer therapeutics and thus optimal patient outcomes.
Background:
Currently, crizotinib is the only drug that has been approved for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). We aimed to study the activity and safety of CH5424802, a potent, selective, and orally available ALK inhibitor.
Methods:
In this multicentre, single-arm, open-label, phase 1-2 study of CH5424802, we recruited ALK inhibitor-naive patients with ALK-rearranged advanced NSCLC from 13 hospitals in Japan. In the phase 1 portion of the study, patients received CH5424802 orally twice daily by dose escalation. The primary endpoints of the phase 1 were dose limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetic parameters. In the phase 2 portion of the study, patients received CH5424802 at the recommended dose identified in the phase 1 portion of the study orally twice a day. The primary endpoint of the phase 2 was the proportion of patients who had an objective response. Treatment was continued in 21-day cycles until disease progression, intolerable adverse events, or withdrawal of consent. The analysis was done by intent to treat. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-101264.
Findings:
Patients were enrolled between Sept 10, 2010, and April 18, 2012. The data cutoff date was July 31, 2012. In the phase 1 portion, 24 patients were treated at doses of 20-300 mg twice daily. No DLTs or adverse events of grade 4 were noted up to the highest dose; thus 300 mg twice daily was the recommended phase 2 dose. In the phase 2 portion of the study, 46 patients were treated with the recommended dose, of whom 43 achieved an objective response (93.5%, 95% CI 82.1-98.6) including two complete responses (4.3%, 0.5-14.8) and 41 partial responses (89.1%, 76.4-96.4). Treatment-related adverse events of grade 3 were recorded in 12 (26%) of 46 patients, including two patients each experiencing decreased neutrophil count and increased blood creatine phosphokinase. Serious adverse events occurred in five patients (11%). No grade 4 adverse events or deaths were reported. The study is still ongoing, since 40 of the 46 patients in the phase 2 portion remain on treatment.
Interpretation:
CH5424802 is well tolerated and highly active in patients with advanced ALK-rearranged NSCLC.
Funding:
Chugai Pharmaceutical Co, Ltd.
With the advent of molecularly “targeted therapies,” most notably the tyrosine kinase inhibitors (TKIs), there has been a significant shift in our formulary from intravenous to orally administered medications. The effect of food on bioavailability is a significant consideration for many drugs, especially those with a narrow therapeutic window. This article focuses on the complicated issue of oncology drug dosing with respect to food, highlighting the impact of food labeling on patient safety.Clinical Pharmacology & Therapeutics (2013); 93 3, 242-244. doi:10.1038/clpt.2012.245
Advanced non-small lung cancer (NSCLC) remains almost uniformly lethal with marginal long-term survival despite efforts to target specific oncogenic addiction pathways that may drive these tumors with small molecularly targeted agents and biologics. The EML4-ALK fusion gene encodes a chimeric tyrosine kinase that activates the Ras signaling pathway, and this fusion protein is found in approximately 5% of NSCLC. Targeting EML4-ALK with Crizotinib in NSCLC has documented therapeutic efficacy, but the vast majority of patients eventually develop recurrent disease that is often refractory to further treatments. We present the clinicopathologic features of three patients with metastatic NSCLC harboring the EML4-ALK translocation that developed isolated central nervous system (CNS) metastases in the presence of good disease control elsewhere in the body. These cases suggest a differential response of NSCLC to Crizotinib in the brain in comparison to other sites of disease, and are consistent with a previous report of poor CNS penetration of Crizotinib. Results of ongoing clinical trials will clarify whether the CNS is a major sanctuary site for EML4-ALK positive NSCLC being treated with Crizotinib. While understanding molecular mechanisms of resistance is critical to overcome therapeutic resistance, understanding physiologic mechanisms of resistance through analyzing anatomic patterns of failure may be equally crucial to improve long-term survival for patients with EML4-ALK translocation positive NSCLC.
ALK fusion genes occur in a subset of non-small-cell lung cancers (NSCLCs). We assessed the tolerability and activity of crizotinib in patients with NSCLC who were prospectively identified to have an ALK fusion within the first-in-man phase 1 crizotinib study.
In this phase 1 study, patients with ALK-positive stage III or IV NSCLC received oral crizotinib 250 mg twice daily in 28-day cycles. Endpoints included tumour responses, duration of response, time to tumour response, progression-free survival (PFS), overall survival at 6 and 12 months, and determination of the safety and tolerability and characterisation of the plasma pharmacokinetic profile of crizotinib after oral administration. Responses were analysed in evaluable patients and PFS and safety were analysed in all patients. This study is registered with ClinicalTrials.gov, number NCT00585195.
Between Aug 27, 2008, and June 1, 2011, 149 ALK-positive patients were enrolled, 143 of whom were included in the response-evaluable population. 87 of 143 patients had an objective response (60·8%, 95% CI 52·3-68·9), including three complete responses and 84 partial responses. Median time to first documented objective response was 7·9 weeks (range 2·1-39·6) and median duration of response was 49·1 weeks (95% CI 39·3-75·4). The response rate seemed to be largely independent of age, sex, performance status, or line of treatment. Median PFS was 9·7 months (95% CI 7·7-12·8). Median overall survival data are not yet mature, but estimated overall survival at 6 and 12 months was 87·9% (95% CI 81·3-92·3) and 74·8% (66·4-81·5), respectively. 39 patients continued to receive crizotinib for more than 2 weeks after progression because of perceived ongoing clinical benefit from the drug (12 for at least 6 months from the time of their initial investigator-defined disease progression). Overall, 144 (97%) of 149 patients experienced treatment-related adverse events, which were mostly grade 1 or 2. The most common adverse events were visual effects, nausea, diarrhoea, constipation, vomiting, and peripheral oedema. The most common treatment-related grade 3 or 4 adverse events were neutropenia (n=9), raised alanine aminotransferase (n=6), hypophosphataemia (n=6), and lymphopenia (n=6).
Crizotinib is well tolerated with rapid, durable responses in patients with ALK-positive NSCLC. There seems to be potential for ongoing benefit after initial disease progression in this population, but a more formal definition of ongoing benefit in this context is needed.
Pfizer.
A majority of the novel orally administered, molecularly targeted anticancer therapies are weak bases that exhibit pH-dependent solubility, and suppression of gastric acidity with acid-reducing agents could impair their absorption. In addition, a majority of cancer patients frequently take acid-reducing agents to alleviate symptoms of gastroesophageal reflux disease, thereby raising the potential for a common but underappreciated drug-drug interaction (DDI) that could decrease the exposure of anticancer medication and result in subsequent failure of therapy. This article is a review of the available clinical literature describing the extent of the interaction between 15 orally administered, small-molecule targeted anticancer therapies and acid-reducing agents. The currently available clinical data suggest that the magnitude of this DDI is largest for compounds whose in vitro solubility varies over the pH range 1-4. This range represents the normal physiological gastric acidity (pH ~1) and gastric acidity while on an acid-reducing agent (pH ~4).
Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered an attractive therapeutic target for human cancers, especially non-small cell lung cancer (NSCLC). Our previous study revealed that 8,9-side-chains of 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole scaffold crucially affected kinase selectivity, cellular activity, and metabolic stability. In this work, we optimized the side-chains and identified highly selective, orally active and potent ALK inhibitor CH5424802 (18a) as the clinical candidate.
Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in certain cancers, following gene alterations such as chromosomal translocation, amplification, or point mutation. Here, we identified CH5424802, a potent, selective, and orally available ALK inhibitor with a unique chemical scaffold, showing preferential antitumor activity against cancers with gene alterations of ALK, such as nonsmall cell lung cancer (NSCLC) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma (ALCL) cells expressing NPM-ALK fusion in vitro and in vivo. CH5424802 inhibited ALK L1196M, which corresponds to the gatekeeper mutation conferring common resistance to kinase inhibitors, and blocked EML4-ALK L1196M-driven cell growth. Our results support the potential for clinical evaluation of CH5424802 for the treatment of patients with ALK-driven tumors.
The EML4 (echinoderm microtubule-associated protein-like 4)-ALK (anaplastic lymphoma kinase) fusion-type tyrosine kinase is an oncoprotein found in 4 to 5% of non-small-cell lung cancers, and clinical trials of specific inhibitors of ALK for the treatment of such tumors are currently under way. Here, we report the discovery of two secondary mutations within the kinase domain of EML4-ALK in tumor cells isolated from a patient during the relapse phase of treatment with an ALK inhibitor. Each mutation developed independently in subclones of the tumor and conferred marked resistance to two different ALK inhibitors. (Funded by the Ministry of Health, Labor, and Welfare of Japan, and others.).
Food can alter the bioavailability of orally administered drugs. Description of food effects in product labels and information about administration in relation to food are influenced by a variety of factors. Because food effects can change drug efficacy and toxicity, it is important that physicians and patients be aware of them.
Several recent oral oncology drugs were labeled for administration in fasted states despite the fact that food increases their bioavailability. Because this was inconsistent with the principles of oral drug delivery, we hypothesized that there were inconsistencies across therapeutic areas.
Oral agents approved by the U.S. Food and Drug Administration from January 2000 to May 2009 were included in our study. Comparison of the food labeling patterns between oncology and non-oncology drugs was made using Fisher's exact test.
Of the 99 drugs evaluated, 34 showed significant food effects on bioavailability. When food markedly enhanced bioavailability, eight out of nine non-oncology drugs were labeled "fed" to take advantage of the food-drug interaction, whereas all oncology drugs (n = 3) were labeled to be administered in "fasted" states (Fisher's exact test, P = 0.01).
Drug labeling patterns with respect to food-drug interactions observed with oncology drugs are in contradiction with fundamental pharmacologic principles, as exemplified in the labeling of non-oncology drugs. .
Nilotinib (Tasigna), a highly selective and potent BCR-ABL tyrosine kinase inhibitor (TKI), is administered orally and has pH-dependent aqueous solubility, with lower dissolution at higher pH. This study evaluated the effect of esomeprazole on the pharmacokinetics of nilotinib in healthy participants. Twenty-two participants (6 women, 16 men, mean age of 44.9 +/- 12.9 years) were enrolled to receive nilotinib as a single oral 400-mg dose on days 1 and 13 and esomeprazole as 40 mg once daily on days 8 to 13. Serial blood samples were collected up to 72 hours after nilotinib dosing, and nilotinib serum concentrations were determined by a validated liquid chromatography/tandem mass spectrometry assay. Gastric pH was also monitored in all participants. When coadministered with esomeprazole, nilotinib C(max) was decreased by 27% and AUC(0-infinity) decreased by 34%. Nilotinib t(max) was prolonged from 4.0 to 6.0 hours, but t(1/2) was not altered. Mean gastric pH was 1.0 +/- 0.5 at baseline and increased to 2.79 +/- 2.50, 3.98 +/- 2.27, 5.30 +/- 1.70, 5.38 +/- 1.26, and 5.31 +/- 1.42 at predose and 1, 2, 3, and 4 hours after the fifth esomeprazole dose, respectively. These results suggested a modest reduction in the rate and extent of nilotinib absorption by esomeprazole. Nilotinib is a TKI that may be used concurrently with esomeprazole or other proton pump inhibitors.