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ABSTRACT: OBJECTIVE: This Phase I study of Fixed Dose Rate (FDR) gemcitabine and carboplatin assessed the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, pharmacokinetic (PK)/pharmacodynamic (PD) profile and preliminary anti-tumor activity in patients with recurrent ovarian cancer (OC). METHODS: Patients with recurrent OC after first line treatment were treated with carboplatin and FDR gemcitabine (infusion speed 10mg/m(2)/min) on days 1, 8 and 15, every 28days. Pharmacokinetics included measurement of platinum concentrations in plasma ultrafiltrate (pUF) and plasma concentrations of gemcitabine (dFdC) and metabolite dFdU. Intracellular levels of dFDC triphposphate (dFdC-TP), the most active metabolite of gemcitabine, were determined in peripheral blood mononuclear cells (PBMCs). Population pharmacokinetic modeling and simulation was performed for the further investigate the optimal schedule. RESULTS: Twenty three patients were enrolled. Initial dose escalation was performed using FDR gemcitabine 300mg/m(2) (administered at infusion speed of 10mg/m(2)/min) combined with carboplatin AUC 2.5 and 3. Excessive bone marrow toxicity led to a modified dose escalation schedule: carboplatin AUC 2 and dose escalation of FDR gemcitabine (300mg/m(2), 450mg/m(2), 600mg/m(2) and 800mg/m(2)). DLT criteria as defined per protocol prior to the study were not met with carboplatin AUC 2 in combination with FDR gemcitabine 300-800mg/m(2) because of myelosuppressive dose-holds (especially thrombocytopenia and neutropenia). CONCLUSIONS: FDR gemcitabine in combination with carboplatin administered in this 28days schedule resulted in increased grade 3/4 toxicity compared to conventional 30-minute infused gemcitabine. A two weekly schedule (chemotherapy on day 1 and 8) would be more appropriate.
Gynecologic Oncology 05/2013; · 3.89 Impact Factor
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ABSTRACT: AIMS: Eribulin mesilate is an inhibitor of microtubule dynamics that is approved for the treatment of late stage metastatic breast cancer. Neutropenia is one of the major dose-limiting adverse effects of eribulin. The objective of this analysis was to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model for eribulin associated neutropenia. METHODS: A combined dataset of 12 phase I, II and III studies for eribulin mesilate was analyzed. The population PK of eribulin was described using a previously developed model. The relationship between eribulin PK and neutropenia was described using a semi-physiological life-span model for hematological toxicity. Patient characteristics predictive of increased sensitivity to develop neutropenia were evaluated using a simulation framework. RESULTS: Absolute neutrophil counts were available from 1579 patients. In the final covariate model, the baseline neutrophil count (ANC0 ) was estimated at 4.03·10(9) neutrophils/L (relative standard error (RSE) 1.2%), with inter-individual variability (IIV, 37.3CV%). The mean transition time (MTT) was estimated at 109 h (RSE 1.8 %, IIV 13.9CV%), the feedback constant (γ) was estimated at 0.216 (RSE 1.4%, IIV 12.2CV%), and the SLOPE was estimated at 0.0451 μg/L (RSE 3.2%, IIV 54CV%). Albumin, aspartate transaminase and G-CSF were identified as significant covariates on SLOPE, and albumin, bilirubin, G-CSF, alkaline phosphatase and lactate dehydrogenase were identified as significant covariates on MTT. CONCLUSION: The developed model can be applied to quantitatively investigate optimal treatment strategies across different patient groups with respect to neutropenia. Albumin was identified as the most clinically important covariate predictive of inter-individual variability in the neutropenia time-course.
British Journal of Clinical Pharmacology 04/2013; · 2.96 Impact Factor
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Bojana Milojkovic Kerklaan,
Veronique Diéras,
Christophe Le Tourneau,
Marja Mergui-Roelvink, Alwin D R Huitema,
Hilde Rosing,
Jos H Beijnen,
Sandrine Marreaud,
Anne-Sophie Govaerts,
Martine J Piccart-Gebhart,
Jan H M Schellens,
Ahmad Awada
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ABSTRACT: PURPOSE: This phase I study was performed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, recommended dose for phase II studies, the pharmacokinetics, and antitumor activity of the combination of lonafarnib (farnesyl transferase inhibitor), trastuzumab, and paclitaxel in Her2-positive advanced breast cancer. METHODS: Twenty-three patients with Her2-overexpressing breast cancer received in the first cycle paclitaxel and trastuzumab and from cycle 2 onwards lonafarnib which was added to the combination. Dose-limiting toxicity (DLT) was determined during the second cycle. RESULTS: The MTD and the recommended dose for phase II trials are lonafarnib: 250 mg/day [125 mg/bi-daily (BID)] continuously, paclitaxel: 175 mg/m² 3-h infusion every 3 weeks, and trastuzumab: 4 mg/kg loading dose and 2 mg/kg/week thereafter. The most frequently observed adverse events starting from cycle 1 onwards were alopecia, myalgia, sensory neuropathy, fatigue, arthralgia, leukocytopenia, and neutropenia. From cycle 2 onwards, additional adverse events appeared, such as diarrhea, nausea, dyspepsia, vomiting, and allergy. The mean systemic exposures of both lonafarnib and paclitaxel through all dose levels were higher in the regimen with all three study medications but with no statistically significant difference. Preliminary antitumor activity (CR + PR) was observed in 58 % of all patients. CONCLUSION: Lonafarnib can be safely combined and tolerated with full doses of paclitaxel and trastuzumab in Her2-positive advanced breast cancer patients. Promising preliminary antitumor activity warrants further evaluation of lonafarnib in combination with paclitaxel and trastuzumab in Her2-positive breast cancer.
Cancer Chemotherapy and Pharmacology 09/2012; · 2.83 Impact Factor
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ABSTRACT: Purpose Trastuzumab treatment is associated with occurrence of cardiac toxicity, for which monitoring of the left ventricular ejection fraction (LVEF) is indicated. The performance of the currently used monitoring protocol as defined in the summary of product characteristics (SPC) is however unknown. The ob-jective of this analysis was to develop a model-based framework for evaluation and optimization of cardiac monitoring strategies. Methods The model-based framework comprised a previous-ly developed exposure-response model for trastuzumab in-duced changes in LVEF, and a protocol-execution model that allowed incorporation of treatment interventions as described by a monitoring protocol. Metrics for evaluation of toxicity, dose intensity and monitoring burden were defined to allow evalua-tion and optimization of cardiac monitoring protocols. Results The success of a protocol-defined dose reduction was improved from 40% for the SPC-based protocol, to 79% for a scoring-based protocol, thereby decreasing the observed severity of cardiotoxicity. Including adaptation based on risk-profile allowed reduction of the mean number of LVEF measurements by 19%. Conclusions This model-based evaluation approach enabled evaluation and optimization of cardiac monitoring protocols that would be difficult to evaluate in a clinical setting. This approach can potentially be applied for other drugs that use repeated evaluation of continuous biomarkers for toxicity.
Pharmaceutical Research 08/2012; · 4.09 Impact Factor
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ABSTRACT: Severe neutropenia is the most frequent and important toxicity of 3-weekly paclitaxel and puts patients at substantial risk of infectious complications. It is well known that the time during which paclitaxel plasma concentrations exceed 0.05 μmol/L (T(C>0.05)) correlates with the extent of neutropenia. This study was initiated to develop a dosing algorithm that would be able to reduce severe neutropenia by targeting an individual paclitaxel T(C>0.05) between 26 and 31 hours, and could be validated in a prospective randomized trial by comparing it to conventional dosing of paclitaxel.
Paclitaxel plasma concentration-time (n = 273) and absolute neutrophil count (ANC) data (152 of the 273 patients) were pooled from two previous studies and submitted to population pharmacokinetic and pharmacodynamic modelling using nonlinear mixed-effects modelling software NONMEM® version VII. To fit the data, we used a previously described 3-compartment model with saturable elimination and distribution, coupled to a semiphysiological model with a linear function to describe the myelotoxic effect of paclitaxel (E(paclitaxel)) on circulating neutrophils (neutropenia). Patient age, sex, body surface area (BSA), bilirubin and renal function were tested as potential covariates on the maximum elimination capacity of paclitaxel (VM(EL)). Limited sampling strategies were tested on the pharmacokinetic model for their accuracy to predict paclitaxel T(C>0.05). Subsequently, we proposed a first-cycle dosing algorithm that accounted for BSA, patient age and sex, while later cycles accounted for the previous-cycle paclitaxel T(C>0.05) (target: 26 to 31 hours) and ANC nadir to adapt the paclitaxel dose for the next treatment cycle. To test the adequacy of the proposed dosing algorithm, we used extensive data simulations on the final pharmacokinetic/pharmacodynamic model, generating datasets of 1000 patients for six subsequent treatment cycles. Grade 4 neutropenia was tested as a potential endpoint for a prospective clinical trial and simulated for two scenarios, i.e. conventional dosing of paclitaxel 200 mg/m(2) every 3 weeks, and personalized, pharmacology-driven dosing as outlined above.
Concentration-time data for paclitaxel were adequately described by the 3-compartment model. Also, individual ANC counts were adequately described by the semiphysiological model using a linear function to describe E(paclitaxel) on neutropenia. Patient age, sex, bilirubin and BSA were significant and independent covariates on the elimination of paclitaxel. Paclitaxel VM(EL) was 16% higher in males than in female patients, and a 10-year increase in age led to a 13% decrease in VM(EL). A single paclitaxel plasma concentration 24 hours after the start of infusion was adequate to predict paclitaxel T(C>0.05) (root squared mean error [RSME] = +0.5%), and the addition of an end-of-infusion sample did not further improve precision (RSME = -0.6%). Data simulations on the final pharmacokinetic/pharmacodynamic model and using the proposed dosing algorithm resulted in a first-cycle paclitaxel dose ranging from 150 to 185 mg/m(2) for women and from 165 to 200 mg/m(2) for men. Dose adaptations for cycles two to six ranged from -40% to +30%, with a final median paclitaxel dose of 167 mg/m(2) (range 76 to 311 mg/m(2)). When compared with conventional dosing (paclitaxel 200 mg/m(2) every 3 weeks), personalized dosing reduced grade 4 neutropenia in cycle one from 15% to 7%, and further to 4% in cycle 2.
This study proposes a pharmacology-driven dosing algorithm of 3-weekly paclitaxel to reduce the incidence of grade 4 neutropenia. A randomized clinical trial comparing this dosing algorithm with conventional BSA-based dosing of paclitaxel in patients with advanced non-small cell lung cancer is currently ongoing.
Clinical Pharmacokinetics 07/2012; 51(9):607-17. · 5.40 Impact Factor
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ABSTRACT: In population pharmacokinetic analyses, missing categorical data are often encountered. We evaluated several methods of performing covariate analyses with partially missing categorical covariate data. Missing data methods consisted of discarding data (DROP), additional effect parameter for the group with missing data (EXTRA), and mixture methods in which the mixing probability was fixed to the observed fraction of categories (MIX(obs)), based on the likelihood of the concentration data (MIX(conc)), or combined likelihood of observed covariate data and concentration data (MIX(joint)). Simulations were implemented to study bias and imprecision of the methods in datasets with equal-sized and unbalanced category ratios for a binary covariate as well as datasets with non-random missingness (MNAR). Additionally, the performance and feasibility of implementation was assessed in two real datasets. At either low (10%) or high (50%) levels of missingness, all methods performed similarly well. Performance was similar for situations with unbalanced datasets (3:1 covariate distribution) and balanced datasets. In the MNAR scenario, the MIX methods showed a higher bias in the estimation of CL and covariate effect than EXTRA. All methods could be applied to real datasets, except DROP. All methods perform similarly at the studied levels of missingness, but the DROP and EXTRA methods provided less bias than the mixture methods in the case of MNAR. However, EXTRA was associated with inflated type I error rates of covariate selection, while DROP handled data inefficiently.
The AAPS Journal 05/2012; 14(3):601-11. · 5.09 Impact Factor
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ABSTRACT: Only anecdotal data are available on the pharmacokinetics (PK) of miltefosine in children suffering from visceral leishmaniasis (VL). While failure rates were higher in children with VL, steady-state concentrations appeared lower than those seen with adults. We hypothesized that the current linear dosage (in milligrams per kilogram of body weight) is too low for children and that a new dosing algorithm based on an appropriate body size model would result in an optimal exposure. A population PK analysis was performed on three historic pooled data sets, including Indian children, Indian adults, and European adults. Linear and allometric scaling of PK parameters by either body weight or fat-free mass (FFM) was evaluated for body size models. Based on the developed PK model, a dosing algorithm for miltefosine in children and adults was proposed and evaluated in silico. The population PK model employing allometric scaling fitted best to the pooled miltefosine data. Allometric scaling by FFM reduced between-subject variability, e.g., for drug clearance, from 49.6% to 32.1%. A new allometric miltefosine dosing algorithm was proposed. Exposure to miltefosine was lower in children than adults receiving 2.5 mg/kg/day: a C(max) of 18.8 μg/ml was reached by 90% of adults and 66.7% of children. The allometric daily dose resulted in similar levels of exposure to miltefosine for adults and children. The use of a new allometric dosing algorithm for miltefosine in VL patients results in optimal exposure to miltefosine in both adults and children and might improve clinical outcome in children.
Antimicrobial Agents and Chemotherapy 05/2012; 56(7):3864-72. · 4.84 Impact Factor
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ABSTRACT: Use of miltefosine in the treatment of visceral leishmaniasis (VL) is hampered by its potential teratogenicity. The duration of adequate contraceptive cover in females of child-bearing potential after cessation of a potentially teratogenic drug therapy remains debated. The objective of this study was to provide a rational approach to suggest durations of contraceptive cover for various miltefosine regimens.
A human reproductive safety threshold exposure limit was derived using animal-to-human dose conversion. Pharmacokinetic (PK) data for miltefosine in females are lacking; a previously developed population PK model and a comprehensive anthropometric dataset were used to simulate PK data for Indian female VL patients receiving miltefosine for 5, 7, 10 or 28 days. Probability of supra-threshold miltefosine exposure was used to evaluate adequate durations of post-treatment contraceptive cover for the various regimens.
PK data were simulated for 465 treated Indian female VL patients of child-bearing potential with a median age of 25 years (IQR 16-31 years) and median weight of 38 kg (IQR 34-42 kg). From animal reproductive toxicity studies, a human reproductive safety threshold exposure limit was derived of 24.5 μg · day/mL. Probability of 'unprotected' supra-threshold miltefosine exposure was very low (<0.2%) for a post-treatment contraceptive cover period of 4 months for the standard 28 day regimen, and of 2 months for the shorter regimens.
To our knowledge, this is the first study providing rational suggestions for contraceptive cover for a teratogenic drug based on animal-to-human dose conversion. For the 28 day miltefosine regimen, post-treatment contraceptive cover may be extended to 4 months, whereas for all shorter regimens 2 months may be adequate.
Journal of Antimicrobial Chemotherapy 05/2012; 67(8):1996-2004. · 5.07 Impact Factor
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ABSTRACT: Plasma concentrations are frequently used for therapeutic drug monitoring of antiretroviral drugs. Dried blood spot sampling offers a patient-friendly and easy alternative to plasma sampling. However, dried blood spot concentrations are not necessarily equal to plasma concentrations and therefore the objective of this work was to establish the relationship between nevirapine and efavirenz dried blood spot and plasma concentrations to facilitate clinical implementation of dried blood spot sampling.
Paired dried blood spot and plasma samples were obtained from 40 HIV-infected patients on nevirapine and 40 on efavirenz treatment. All samples were analysed using validated HPLC-tandem mass spectrometry methods for the two matrices. Theoretical plasma concentrations were calculated from dried blood spot concentrations using the formula [dried blood spot concentration/(1 - haematocrit)] × fraction bound to plasma proteins = plasma concentration. Linear regression and Bland-Altman analysis were used to compare the two methods.
Dried blood spot and plasma concentrations of nevirapine and efavirenz correlated well (r(2) = 0.867 and 0.972, respectively), although efavirenz dried blood spot concentrations were 39.8% (SD 7.1%) lower than plasma concentrations. Theoretical plasma concentrations (using patient-specific haematocrit) of nevirapine and efavirenz were similar to measured plasma concentrations, with a mean difference between the two methods of 0.29 mg/L (SD 1.35 mg/L) and 0.08 mg/L (SD 0.31 mg/L), respectively.
Dried blood spot concentrations of nevirapine and efavirenz were equal to plasma concentrations after correction for haematocrit and compound-specific plasma protein binding and can therefore be used in clinical practice.
Journal of Antimicrobial Chemotherapy 02/2012; 67(5):1211-6. · 5.07 Impact Factor
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Anne-Charlotte Dubbelman,
Hilde Rosing,
Robert S Jansen,
Marja Mergui-Roelvink, Alwin D R Huitema,
Barbara Koetz,
Margarita Lymboura,
Larisa Reyderman,
Arturo Lopez-Anaya,
Jan H M Schellens,
Jos H Beijnen
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ABSTRACT: This mass balance study investigated the metabolism and excretion of eribulin, a nontaxane microtubule dynamics inhibitor with a novel mechanism of action, in patients with advanced solid tumors. A single approximately 2 mg (approximately 80 μCi) dose of [¹⁴C]eribulin acetate was administered as a 2 to 5 min bolus injection to six patients on day 1. Blood, urine, and fecal samples were collected at specified time points on days 1 to 8 or until sample radioactivity was ≤1% of the administered dose. Mean plasma eribulin exposure (627 ng · h/ml) was comparable with that of total radioactivity (568 ng Eq · h/ml). Time-matched concentration ratios of eribulin to total radioactivity approached unity in blood and plasma, indicating that unchanged parent compound constituted almost all of the eribulin-derived radioactivity. Only minor metabolites were detected in plasma samples up to 60 min postdose, pooled across patients, each metabolite representing ≤0.6% of eribulin. Elimination half-lives for eribulin (45.6 h) and total radioactivity (42.3 h) were comparable. Eribulin-derived radioactivity excreted in feces was 81.5%, and that of unchanged eribulin was 61.9%. Renal clearance (0.301 l/h) was a minor component of total eribulin clearance (3.93 l/h). Eribulin-derived radioactivity excreted in urine (8.9%) was comparable with that of unchanged eribulin (8.1%), indicating minimal excretion of metabolite(s) in urine. Total recovery of the radioactive dose was 90.4% in urine and feces. Overall, no major metabolites of eribulin were detected in plasma. Eribulin is eliminated primarily unchanged in feces, whereas urine constitutes a minor route of elimination.
Drug metabolism and disposition: the biological fate of chemicals 02/2012; 40(2):313-21. · 3.74 Impact Factor
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Journal of palliative care 01/2012; 28(1):60-1. · 0.93 Impact Factor
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ABSTRACT: Skin reactions are side effects of sunitinib therapy with an adverse impact on quality of life often necessitating dose reductions. For conventional antineoplastic agents, such as doxorubicin, previous studies have indicated a possible relationship between sweat excretion and the development of skin toxicity. However, the determination of sunitinib and its active metabolite in sweat has not yet been reported. A sensitive and accurate method for the determination of sunitinib and its active metabolite N-desethylsunitinib in human sweat was developed using high-performance liquid chromatography coupled to tandem mass spectrometry detection (LC-MS-MS). Sweat samples of a patient treated with sunitinib were collected using Pharmchek™ Drugs of Abuse patches to determine cumulative amounts of sunitinib and metabolite. Validation of the LC-MS-MS method was performed over a range from 1.0 to 200 ng/patch with good intra- and interassay accuracies for sunitinib and N-desethylsunitinib. Ranges of 76-119 and 7.9-10.5 ng/patch for cumulative secretion of sunitinib and metabolite, respectively, were found in patient samples. To our knowledge, this is the first method for determination of cumulative secretion of sunitinib and N-desethylsunitinib in human sweat samples. Sunitinib and its metabolite were easily detectable in sweat patches of a patient treated with sunitinib.
Journal of analytical toxicology 10/2011; 35(8):558-65. · 2.02 Impact Factor
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Markus Joerger,
Sjaak A Burgers,
Paul Baas,
Egbert F Smit,
Tjeerd J Haitjema,
Martin P L Bard,
Valerie D Doodeman,
Paul H M Smits,
Andrew Vincent, Alwin D R Huitema,
Jos H Beijnen,
Jan H M Schellens
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ABSTRACT: The authors assessed the impact of germline polymorphisms on clinical outcome in patients with advanced nonsmall cell lung cancer (NSCLC) who received platinum-gemcitabine (PG) chemotherapy.
In total, 137 patients with stage IIIB/IV NSCLC were included who received first-line PG chemotherapy (74% of patients received cisplatin, and 26% received carboplatin). Twenty-three germline polymorphisms that were identified in peripheral blood samples were analyzed for progression-free survival (PFS), treatment response, overall survival (OS), and toxicity.
The median PFS was 5.8 months, the median OS was 10.2 months, and 44 patients (32%) had a partial treatment response. Carriers of the excision repair cross-complementation group 1 (ERCC1) mutant thymine (T) allele had a lower treatment response rate (29% vs 52%; P = .02), shorter PFS (adjusted hazard ratio [HR], 1.60; P = .04), and shorter OS (adjusted HR, 1.54; P = .05) compared with carriers of the wild-type cytosine/cytosine (CC) genotype. The xeroderma pigmentosum group A member 10 (XPD10) mutant adenine (A) allele (adjusted HR, 0.64; P = .04) and the x-ray cross-complementing group 1 (XRCC1) mutant guanine (G) allele (adjusted HR, 0.51; P = .02) also were independent predictors of OS. Carriers of the mutant adenosine triphosphate-dependent DNA helicase Q1 (RECQ1) C allele or the mutant cytidine deaminase (CDA) C allele were more likely to experience severe leukocytopenia (26% vs 10% [P = .03] and 28% vs 11% [P = .02], respectively) compared with wild-type genotype carriers. Patients who carried the homozygous mutant glutathione S-transferase π 1(GSTP1) GG genotype were at considerable risk for severe platinum-associated polyneuropathy (18% vs 3% in wild-type vs heterozygous mutant patients, respectively; P = .01).
To the authors' knowledge, this is the first prospective study to date in patients with advanced NSCLC describing predictive germline polymorphisms not only for the clinical activity of PG chemotherapy (ERCC1, XPD10) but also for its toxicity (GSTP1, RECQ1, CDA). Nonplatinum-containing chemotherapy in carriers of the ERCC1 T allele or the XPD10 G allele should be studied prospectively.
Cancer 09/2011; 118(9):2466-75. · 4.77 Impact Factor
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ABSTRACT: Lopinavir, a human immunodeficiency virus protease inhibitor, has a very low oral bioavailability, which can be enhanced with a low dose of the CYPA4 inhibitor ritonavir. Our aim was to separately quantify the role of intestinal and hepatic cytochrome P450 3A (CYP3A4) expression on lopinavir disposition in a novel mouse model. Lopinavir and ritonavir were administered to mice selectively expressing human CYP3A4 in the intestine and/or liver. Using nonlinear mixed-effects modeling, we could separately quantify the effects of intestinal CYP3A4 expression, hepatic CYP3A4 expression, and the presence of ritonavir on both the absorption and elimination of lopinavir, which was previously not possible using noncompartmental methods. Intestinal, but not hepatic, CYP3A4-related first-pass metabolism was the major barrier for systemic entry of lopinavir. Relative oral bioavailability of lopinavir in mice expressing both hepatic and intestinal CYP3A4 was only 1.3% when compared with mice that were CYP3A deficient. In presence of ritonavir, relative bioavailability increased to 9.5% due to inhibiton of intestinal, but not due to inhibition of hepatic first-pass metabolism. Hepatic CYP3A4 related systemic clearance was inversely related to ritonavir exposure and not only hepatic but also intestinal CYP3A4 expression contributed to systemic clearance of lopinavir.
Journal of Pharmaceutical Sciences 06/2011; 100(6):2508-15. · 3.06 Impact Factor
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ABSTRACT: Modeling and simulation of pharmacokinetics and pharmacodynamics has previously been shown to be potentially useful in designing Phase I programs of novel anti-cancer agents that show hematological toxicity. In this analysis, a two-stage model-based trial design was evaluated retrospectively using data from the Phase I program with the aurora kinase inhibitor barasertib.
Data from two Phase I trials and four regimens were used (n = 79). Using barasertib-hydroxy QPA plasma concentrations and neutrophil count data from only study 1A, a PKPD model was developed and subsequently used to predict the MTD and a safe starting dose for the other trials.
The PKPD model based on data from the first study adequately described the time course of neutrophil count fluctuation. The two-stage model-based design provided safe starting doses for subsequent phase I trials for barasertib. Predicted safe starting dose levels were higher than those used in two subsequent trials, but lower than used in the other trial.
The two-stage approach could have been applied safely to define starting doses for alternative dosing strategies with barasertib. The limited improvement in efficiency for the phase I program of barasertib may have been due to the fact that starting doses for the studied phase I trials were already nearly optimal.
Application of the two-stage model-based trial design in Phase I programs with novel anti-cancer drugs that cause haematological toxicity is feasible, safe, and may lead to a reduction in the number of patient treated at sub-therapeutic dose-levels.
Investigational New Drugs 05/2011; 30(4):1519-30. · 3.36 Impact Factor
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Journal of child and adolescent psychopharmacology 02/2011; 21(1):93-5. · 2.59 Impact Factor
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ABSTRACT: A novel formulation of C1 esterase inhibitor concentrate, a plasma product used in the treatment of hereditary angioedema (HAE), was studied in a clinical trial for similarity in pharmacokinetics (PK) compared with the reference product. Direct trial data were limited given the availability of patients, and therefore a modeling approach was used to study similarity. Type I error of the study was evaluated using simulations based on retrospective data. A population PK modeling analysis was performed on data from the trial. Analysis of variance was carried out on results of a noncompartmental PK analysis (NCA) of the clinical data. Simulations showed that type I error was inflated to 62% (P < .05) when bioequivalence criteria (confidence intervals within 80%-125%) were adhered to strictly. In the clinical trial, 13 HAE patients were evaluable. The population PK analysis showed no significant differences in PK parameters, whereas confidence intervals for all parameters were within 80% to 125%. The relative differences in area under the curve, incremental recovery, and mean residence time estimated using NCA were all close to 1. The novel formulation showed similar PK characteristics to the original formulation. The model-based approach showed that strict criteria for PK comparison could not be applied in this analysis.
The Journal of Clinical Pharmacology 01/2011; · 2.91 Impact Factor
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ABSTRACT: Pharmacokinetic-pharmacodynamic modeling using non-linear mixed effects modeling (NONMEM) is a powerful yet challenging technique, as the software is generally accessed from the command line. A graphical user interface, Piraña, was developed that offers a complete modeling environment for NONMEM, enabling both novice and advanced users to increase efficiency of their workflow. Piraña provides features for the management and creation of model files, the overview of modeling results, creation of run reports and handling of datasets and output tables, and the running of custom R scripts on model output. Through the secure shell (SSH) protocol, Piraña can also be used to connect to Linux clusters (SGE, MOSIX) for distribution of workload. Modeling with NONMEM is computationally burdensome, which may be alleviated by distributing runs to computer clusters. A solution to this problem is offered here, called PCluster. This platform is easy to set up, runs in standard network environments, and can be extended with additional nodes if needed. The cluster supports the modeling toolkit Perl speaks NONMEM (PsN), and can include dedicated or non-dedicated PCs. A daemon script, written in Perl, was designed to run in the background on each node in the cluster, and to manage job distribution. The PCluster can be accessed from Piraña, and both software products have extensively been tested on a large academic network. The software is available under an open-source license.
Computer methods and programs in biomedicine 01/2011; 101(1):72-9. · 1.14 Impact Factor
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ABSTRACT: Hypertension and proteinuria are commonly observed side-effects for anti-angiogenic drugs targeting the VEGF pathway. In most cases, hypertension can be controlled by prescription of anti-hypertensive (AH) therapy, while proteinuria often requires dose reductions or dose delays. We aimed to construct a pharmacokinetic-pharmacodynamic (PK-PD) model for hypertension and proteinuria following treatment with the experimental VEGF-inhibitor E7080, which would allow optimization of treatment, by assessing the influence of anti-hypertensive medication and dose reduction or dose delays in treating and avoiding toxicity. Data was collected from a phase I study of E7080 (n = 67), an inhibitor of multiple tyrosine kinases, among which VEGF. Blood pressure and urinalysis data were recorded weekly. Modeling was performed in NONMEM, and direct and indirect response PK-PD models were evaluated. A previously developed PK model was used. An indirect response PK-PD model described the increase in BP best, while the probability of developing proteinuria toxicity in response to exposure to E7080, was best described by a Markov transition model. This model may guide clinical interventions and provide treatment recommendations for E7080, and may serve as a template model for other drugs in this class.
Journal of Pharmacokinetics and Biopharmaceutics 08/2010; 37(4):347-63. · 2.06 Impact Factor
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ABSTRACT: Monoclonal antibodies (mAbs) have been used in the treatment of various diseases for over 20 years and combine high specificity with generally low toxicity. Their pharmacokinetic properties differ markedly from those of non-antibody-type drugs, and these properties can have important clinical implications. mAbs are administered intravenously, intramuscularly or subcutaneously. Oral administration is precluded by the molecular size, hydrophilicity and gastric degradation of mAbs. Distribution into tissue is slow because of the molecular size of mAbs, and volumes of distribution are generally low. mAbs are metabolized to peptides and amino acids in several tissues, by circulating phagocytic cells or by their target antigen-containing cells. Antibodies and endogenous immunoglobulins are protected from degradation by binding to protective receptors (the neonatal Fc-receptor [FcRn]), which explains their long elimination half-lives (up to 4 weeks). Population pharmacokinetic analyses have been applied in assessing covariates in the disposition of mAbs. Both linear and nonlinear elimination have been reported for mAbs, which is probably caused by target-mediated disposition. Possible factors influencing elimination of mAbs include the amount of the target antigen, immune reactions to the antibody and patient demographics. Bodyweight and/or body surface area are generally related to clearance of mAbs, but clinical relevance is often low. Metabolic drug-drug interactions are rare for mAbs. Exposure-response relationships have been described for some mAbs. In conclusion, the parenteral administration, slow tissue distribution and long elimination half-life are the most pronounced clinical pharmacokinetic characteristics of mAbs.
Clinical Pharmacokinetics 08/2010; 49(8):493-507. · 5.40 Impact Factor
