Jos H Beijnen

Slotervaartziekenhuis, Amsterdamo, North Holland, Netherlands

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Publications (738)2792.03 Total impact

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    ABSTRACT: Recently, there has been a renewed interest in the development of new drugs for the treatment of leishmaniasis. This has spurred the need for pharmacodynamic markers to monitor and compare therapies specifically for visceral leishmaniasis, in which the primary recrudescence of parasites is a particularly long-term event that remains difficult to predict. We performed a systematic review of studies evaluating biomarkers in human patients with visceral, cutaneous, and post-kala-azar dermal leishmaniasis, which yielded a total of 170 studies in which 53 potential pharmacodynamic biomarkers were identified. In conclusion, the large majority of these biomarkers constituted universal indirect markers of activation and subsequent waning of cellular immunity and therefore lacked specificity. Macrophage-related markers demonstrate favorable sensitivity and times to normalcy, but more evidence is required to establish a link between these markers and clinical outcome. Most promising are the markers directly related to the parasite burden, but future effort should be focused on optimization of molecular or antigenic targets to increase the sensitivity of these markers. In general, future research should focus on the longitudinal evaluation of the pharmacodynamic biomarkers during treatment, with an emphasis on the correlation of studied biomarkers and clinical parameters.
    Antimicrobial Agents and Chemotherapy 12/2015; 59(1):1-14. DOI:10.1128/AAC.04298-14 · 4.45 Impact Factor
  • Therapeutic drug monitoring 05/2015; DOI:10.1097/FTD.0000000000000224 · 1.93 Impact Factor
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    ABSTRACT: The antiestrogenic drug tamoxifen is widely used in the treatment of estrogen receptor-α-positive breast cancer and substantially decreases recurrence and mortality rates. However, high interindividual variability in response is observed, calling for a personalized approach to tamoxifen treatment. Tamoxifen is bioactivated by cytochrome P450 (CYP) enzymes such as CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5, resulting in the formation of active metabolites, including 4-hydroxy-tamoxifen and endoxifen. Therefore, polymorphisms in the genes encoding these enzymes are proposed to influence tamoxifen and active tamoxifen metabolites in the serum and consequently affect patient response rates. To tailor tamoxifen treatment, multiple studies have been performed to clarify the influence of polymorphisms on its pharmacokinetics and pharmacodynamics. Nevertheless, personalized treatment of tamoxifen based on genotyping has not yet met consensus. This article critically reviews the published data on the effect of various genetic polymorphisms on the pharmacokinetics and pharmacodynamics of tamoxifen, and reviews the clinical implications of its findings. For each CYP enzyme, the influence of polymorphisms on pharmacokinetic and pharmacodynamic outcome measures is described throughout this review. No clear effects on pharmacokinetics and pharmacodynamics were seen for various polymorphisms in the CYP encoding genes CYP2B6, CYP2C9, CYP2C19 and CYP3A4/5. For CYP2D6, there was a clear gene-exposure effect that was able to partially explain the interindividual variability in plasma concentrations of the pharmacologically most active metabolite endoxifen; however, a clear exposure-response effect remained controversial. These controversial findings and the partial contribution of genotype in explaining interindividual variability in plasma concentrations of, in particular, endoxifen, imply that tailored tamoxifen treatment may not be fully realized through pharmacogenetics of metabolizing enzymes alone.
    Clinical Pharmacokinetics 05/2015; DOI:10.1007/s40262-015-0273-3 · 5.49 Impact Factor
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    ABSTRACT: Enhancer of Zeste Homolog 2 (EZH2) has emerged as a promising therapeutic target for treatment of a broad spectrum of tumors including gliomas. We explored the interactions of five novel, structurally similar EZH2 inhibitors (EPZ005687, EPZ-6438, UNC1999, GSK343 and GSK126) with P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2). The compounds were screened by in vitro transwell assays and EPZ005687, EPZ-6438 and GSK126 were further tested in vivo using wild-type (WT), Abcb1 and/or Abcg2 knockout mice. All EZH2 inhibitors are transported by P-gp and BCRP, although in vitro the transporter affinity of GSK126 was obscured by very low membrane permeability. Both P-gp and Bcrp1 restrict the brain penetration of EPZ005687 and GSK126, whereas the brain accumulation of EPZ-6438 is limited by P-gp only and efflux of EPZ-6438 was completely abrogated by elacridar. Intriguingly, an unknown factor present in all knockout mouse strains causes EPZ005687 and EPZ-6438 retention in plasma relative to WT mice, a phenomenon not seen with GSK126. In WT mice, the GSK126 tissue-to-plasma ratio for all tissues is lower than for EPZ005687 or EPZ-6438. Moreover, the oral bioavailability of GSK126 is only 0.2% in WT mice, which increase to 14.4% in Abcb1;Abcg2 knockout mice. These results are likely due to poor membrane permeability and question the clinical usefulness of GSK126. Although all tested EZH2 inhibitors are substrates of P-gp and BCRP, restricting the brain penetration and potential utility for treatment of glioma, EPZ-6438 would be the most suitable candidate of this series. This article is protected by copyright. All rights reserved. © 2015 UICC.
    International Journal of Cancer 04/2015; DOI:10.1002/ijc.29566 · 5.01 Impact Factor
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    ABSTRACT: Small molecular tyrosine kinase inhibitors (smTKIs) are in the centre of the very quickly expanding area of personalized chemotherapy and oral applicability thereof. The number of drugs in this class is rapidly growing, with twenty current approvals by both the European Medicines Agency (EMA) and the Food and Drug Administration (FDA). The drugs are, however, generally characterized by a poor oral, and thus variable, bioavailability. This results in significant variation in plasma levels and exposure. The cause is a complex interplay of factors, including poor aqueous solubility, issued permeability, membrane transport and enzymatic metabolism. Additionally, food and drug-drug interactions can play a significant role. The issues related with an impaired bioavailability generally receive little attention. To the best of our knowledge, this article is the first to provide an overview of the factors that determine the bioavailability of the smTKIs. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Cancer Treatment Reviews 03/2015; 41(5). DOI:10.1016/j.ctrv.2015.03.005 · 6.47 Impact Factor
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    ABSTRACT: 5-Fluorouracil (5-FU) and its oral prodrug capecitabine are among the most widely used chemotherapeutics. For cytotoxic activity, 5-FU requires cellular uptake and intracellular metabolic activation. Three intracellular formed metabolites are responsible for the antineoplastic effect of 5-FU: 5-fluorouridine 5'-triphosphate (FUTP), 5-fluoro-2'-deoxyuridine 5'-triphosphate (FdUTP) and 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP). In this paper, we describe the development of an LC-MS/MS assay for quantification of these active 5-FU nucleotides in peripheral blood mononuclear cells (PBMCs). Because the intracellular 5-FU nucleotide concentrations were very low, maximization of the release from the cell matrix and minimization of interference were critical factors. Therefore, a series of experiments was performed to select the best method for cell lysis and nucleotide extraction. Chromatography was optimized to obtain separation from endogenous nucleotides, and the effect of different cell numbers was examined. The assay was validated for the following concentration ranges in PBMC lysate: 0.488-19.9nM for FUTP, 1.66-67.7nM for FdUTP and 0.748-30.7nM for FdUMP. Accuracies were between -2.2 and 7.0% deviation for all analytes, and the coefficient of variation values were ≤4.9%. The assay was successfully applied to quantify 5-FU nucleotides in PBMC samples from patients treated with capecitabine and patients receiving 5-FU intravenously. FUTP amounts up to 3054fmol/10(6) PBMCs and FdUMP levels up to 169fmol/10(6) PBMCs were measured. The FdUTP concentrations were below the lower limit of quantification. To our knowledge, this is the first time that 5-FU nucleotides were quantified in cells from patients treated with 5-FU or capecitabine without using a radiolabel. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of pharmaceutical and biomedical analysis 03/2015; 110:58-66. DOI:10.1016/j.jpba.2015.02.051 · 2.83 Impact Factor
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    ABSTRACT: Handling of data below the lower limit of quantification (LLOQ), below the limit of quantification (BLOQ) in population pharmacokinetic (PopPK) analyses is important for reducing bias and imprecision in parameter estimation. We aimed to evaluate whether using the concentration data below the LLOQ has superior performance over several established methods. The performance of this approach (“All data”) was evaluated and compared to other methods: “Discard,” “LLOQ/2,” and “LIKE” (likelihood-based). An analytical and residual error model was constructed on the basis of in-house analytical method validations and analyses from literature, with additional included variability to account for model misspecification. Simulation analyses were performed for various levels of BLOQ, several structural PopPK models, and additional influences. Performance was evaluated by relative root mean squared error (RMSE), and run success for the various BLOQ approaches. Performance was also evaluated for a real PopPK data set. For all PopPK models and levels of censoring, RMSE values were lowest using “All data.” Performance of the “LIKE” method was better than the “LLOQ/2” or “Discard” method. Differences between all methods were small at the lowest level of BLOQ censoring. “LIKE” method resulted in low successful minimization (<50%) and covariance step success (<30%), although estimates were obtained in most runs (~90%). For the real PK data set (7.4% BLOQ), similar parameter estimates were obtained using all methods. Incorporation of BLOQ concentrations showed superior performance in terms of bias and precision over established BLOQ methods, and shown to be feasible in a real PopPK analysis.
    03/2015; 3(2). DOI:10.1002/prp2.131
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    ABSTRACT: Dihydropyrimidine dehydrogenase (DPD) activity determination in peripheral blood mononuclear cells of DPD deficient patients was hitherto inaccurate due to hemoglobin (Hb) contamination. We developed an improved method for accurate measurement of DPD activity in patients. DPD activity was determined by HPLC with online radioisotope detection using liquid scintillation counting. Hb was determined spectrophotometrically. Method accuracy and precision were significantly improved by using cumulative area of all peaks as IS. Peripheral blood mononuclear cell lysates from DPD deficient patients were highly contaminated with on average 23.3% (range 2.7-51%) of Hb resulting in up to twofold underestimated DPD activity. DPD activities were corrected for Hb contamination. The method was validated and showed good long-term sample stability. This method has increased specificity allowing accurate identification of DPD deficient patients.
    Bioanalysis 03/2015; 7(5):519-529. DOI:10.4155/bio.14.304 · 3.03 Impact Factor
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    ABSTRACT: To determine the effect of renal impairment and prior platinum-based chemotherapy on the toxicities and pharmacokinetics of oral topotecan and to identify recommended doses for patients with renal impairment or prior platinum-based (PB)-chemotherapy. A multi-center phase I toxicity and pharmacokinetic study of oral topotecan in patients with advanced solid tumors. Patients were grouped by normal renal function with limited- or prior PB-chemotherapy or impaired renal function (mild [creatinine clearance (Clcr) = 50-79 mL/min], moderate [Clcr = 30-49 mL/min], severe [Clcr <30 mL/min]). Fifty-nine patients were evaluable. Topotecan lactone and total topotecan 'area under the concentration-time curve' (AUC) was significantly increased in patients with moderate and severe renal impairment (109% and 174%, respectively, topotecan lactone and 148% and 298%, respectively, total topotecan). Asian patients (23 in total) had higher AUCs than non-Asian patients with the same degree of renal impairment. Thirteen dose-limiting toxicities (DLTs) were observed, which were mostly hematological. The maximum-tolerated dose (MTD) was 2.3 mg/m(2) /day, given on days 1 to 5 in a 21-day cycle, for patients with prior PB-chemotherapy or mild renal impairment, and 1.2 mg/m(2) /day for patients with moderate renal impairment (suggested dose 1.9 mg/m(2) /day for non-Asians). Due to incomplete enrollment of patients with severe renal impairment, the MTD was determined as ≥ 0.6 mg/m(2) /day in this cohort. Oral topotecan dose adjustments are not required in patients with prior PB-chemotherapy or mildly impaired renal function, but reduced doses are required for patients with moderate or severe renal impairment. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 02/2015; DOI:10.1111/bcp.12606 · 3.69 Impact Factor
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    ABSTRACT: No effective targeted therapy is currently available for NRAS mutant melanoma. Experimental MEK inhibition is rather toxic and has only limited efficacy in clinical trials. At least in part, this is caused by the emergence of drug resistance, which is commonly seen for single agent treatment and shortens clinical responses. Therefore, there is a dire need to identify effective companion drug targets for NRAS mutant melanoma. Here, we show that at concentrations where single drugs had little effect, ROCK inhibitors GSK269962A or Fasudil, in combination with either MEK inhibitor GSK1120212 (Trametinib) or ERK inhibitor SCH772984 cooperatively caused proliferation inhibition and cell death in vitro. Simultaneous inhibition of MEK and ROCK caused induction of BimEL , PARP, and Puma, and hence apoptosis. In vivo, MEK and ROCK inhibition suppressed growth of established tumors. Our findings warrant clinical investigation of the effectiveness of combinatorial targeting of MAPK/ERK and ROCK in NRAS mutant melanoma. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Pigment Cell & Melanoma Research 02/2015; 28(3). DOI:10.1111/pcmr.12364 · 5.64 Impact Factor
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    ABSTRACT: A quantitative bioanalytical liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay for GSK2126458, a dual PI3K/mTOR inhibitor, was developed and validated. Plasma and tumor homogenate samples were pre-treated using protein precipitation with acetonitrile containing dabrafenib as internal standard. After dilution with water, the extract was directly injected into the reversed-phase liquid chromatographic system. The eluate was transferred into the electrospray interface with positive ionization and compounds were detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer. The assay was completely validated for plasma in a 4-4000ng/ml calibration range with r(2)=0.9996±0.0003 using double logarithmic calibration (n=5). Within-run precisions (n=6) were 2.0-5.3% and between-run (3 runs; n=18) precisions 2.7-5.8%. Accuracies were between 101 and 105% for the whole calibration range. The drug was sufficiently stable under all relevant analytical conditions. Finally, the assay was successfully applied to determine plasma and tumor drug levels after oral administration of GSK2126458 to mice with AMC711T neuroblastoma xenografts. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of Pharmaceutical and Biomedical Analysis 01/2015; 107C:403-408. DOI:10.1016/j.jpba.2015.01.026 · 2.83 Impact Factor
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    ABSTRACT: Purpose Overdose with baclofen, a derivative of the inhibitory neurotransmitter γ-aminobutyric acid, may lead to severe respiratory and central nervous system depression and can be life-threatening. Prolonged half-lives of baclofen, of up to 34 h, have been reported in patients after overdose. Hemodialysis has proven to be a successful approach to improve clearance of baclofen, but the value of continuous venovenous hemofiltration (CVVH) is unclear. We applied CVVH in a patient with acute baclofen overdose. Methods Pharmacokinetic measurements of baclofen in serum and hemofiltrate were made at six time points after hospital admission. Baclofen concentration-time data were analyzed using non-compartmental methods, and the relative contribution of clearance by hemofiltration to total baclofen clearance was calculated. Results Baclofen concentrations in serum varied between 1.81 and 0.05 mg/L. Concentrations of baclofen in hemofiltrate were within the same range (between 0.74 and 0.05 mg/L), and the elimination half-life during hemofiltration was estimated at 4.8 h. Total clearance and clearance via hemofiltration were estimated at 6.6 and 2.4 L/h, indicating that clearance could be increased by approximately 57 % by applying hemofiltration. Conclusions The presented case demonstrates the usefulness of CVVH in the treatment of baclofen overdose and indicates that CVVH can be used as an alternative to hemodialysis in patients with overdose of baclofen.
    European Journal of Clinical Pharmacology 01/2015; 71(3). DOI:10.1007/s00228-014-1802-y · 2.70 Impact Factor
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    ABSTRACT: Regorafenib is a novel multikinase inhibitor, currently approved for the treatment of metastasized colorectal cancer and advanced gastrointestinal stromal tumors. We investigated whether regorafenib is a substrate for the multidrug efflux transporters ABCG2 and ABCB1 and whether oral availability, brain and testis accumulation of regorafenib and its active metabolites are influenced by these transporters. We used in vitro transport assays to assess human (h)ABCB1- or hABCG2- or murine (m)Abcg2-mediated active transport at high and low concentrations of regorafenib. To study the single and combined roles of Abcg2 and Abcb1a/1b in oral regorafenib disposition and the impact of Cyp3a-mediated metabolism, we used appropriate knockout mouse strains. Regorafenib was transported well by mAbcg2 and hABCG2 and modestly by hABCB1 in vitro. Abcg2 and to a lesser extent Abcb1a/1b limited brain and testis accumulation of regorafenib and metabolite M2 (brain only) in mice. Regorafenib oral availability was not increased in Abcg2 (-/-) ;Abcb1a/1b (-/-) mice. Up till 2 h, metabolite M5 was undetectable in plasma and organs. Brain and testis accumulation of regorafenib and brain accumulation of metabolite M2 are restricted by Abcg2 and Abcb1a/1b. Inhibition of these transporters may be of clinical relevance for patients with brain (micro)metastases positioned behind an intact blood-brain barrier.
    Pharmaceutical Research 01/2015; 32(7). DOI:10.1007/s11095-014-1609-7 · 3.95 Impact Factor
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    ABSTRACT: Following bariatric surgery, patients are expected to implement diet and lifestyle changes that may be imitated by cohabitating family members. We hypothesize that cohabitating family members will lose weight and improve their eating behavior within 1 year after surgery. In this observational prospective study, family members of patients who had gastric bypass surgery (88 partners, 20 children ≥18 years old, and 25 children between 12 and 17 years old) were repeatedly assessed. Family members were asked to assess their weight and height before and 3, 6, and 12 months following bariatric surgery, and they filled out the Dutch Eating Behavior Questionnaire. Between baseline and 1 year following surgery, 49 partners of patients who underwent gastric bypass surgery (66.2%) lost weight, 6 (8.1%) remained stable, and 19 (25.7%) gained weight. Body mass index of partners (P = .002), particularly of overweight partners (P < .001)-but not children-showed a small, significant decrease over time. No significant changes in eating behavior among partners or children were found. The study indicates that gastric bypass surgery may have a ripple effect, with body weight in partners of patients decreasing over time. However, there is considerable variation in the postoperative weight loss of partners. © Copyright 2015 by the American Board of Family Medicine.
    The Journal of the American Board of Family Medicine 01/2015; 28(1):90-6. DOI:10.3122/jabfm.2015.01.140103 · 1.85 Impact Factor
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    ABSTRACT: Organic Anion Transporting Polypeptides (human: OATPs, mouse: Oatps) are uptake transporters with important roles in drug pharmacokinetics and toxicity. We aimed to study the in vivo impact of mouse and human OATP1A/1B transporters on docetaxel plasma clearance and liver and intestinal uptake. Docetaxel was administered to Oatp1a/1b knockout and liver-specific humanized OATP1B1, OATP1B3 and OATP1A2 transgenic mice. Experiments were conducted with a low polysorbate 80 (2.8%) formulation, as 8% polysorbate somewhat inhibited docetaxel plasma clearance after intravenous administration. After intravenous administration (10 mg/kg), Oatp1a/1b knockout mice had a ~3-fold higher plasma AUC. Impaired liver uptake was evident from the significantly reduced (~3-fold) liver-to-plasma AUC ratios. Absence of mouse Oatp1a/1b transporters did not affect the intestinal absorption of orally administered docetaxel (10 mg/kg), while the systemic exposure of docetaxel was again substantially increased due to impaired liver uptake. Most importantly, liver-specific expression of each of the human OATP1B1, OATP1B3 and OATP1A2 transporters provided a nearly complete rescue of the increased plasma levels of docetaxel in Oatp1a/1b-null mice after intravenous administration. Our data show that one or more of the mouse Oatp1a/1b transporters and each of the human OATP1A/1B transporters can mediate docetaxel uptake in vivo. This might be clinically relevant for OATP1A/1B-mediated tumor uptake of docetaxel and for docetaxel clearance in patients in which the transport activity of OATP1A/1B transporters is reduced due to genetic variation or pharmacological inhibition, leading to potentially altered toxicity and therapeutic efficacy of this drug. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 01/2015; 136(1). DOI:10.1002/ijc.28970 · 5.01 Impact Factor
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    ABSTRACT: To further investigate the pharmacokinetics of vemurafenib and to support therapeutic drug monitoring an LC-MS/MS method was developed and validated for the quantification of vemurafenib in dried blood spots. Vemurafenib was extracted from the dried blood spots by methanol:acetonitrile (50:50, v/v) and separated on a C18 column with gradient elution and analyzed with triple quadrupole mass spectrometry in positive ion mode. The validated calibration range is linear from 1 to 100 µg/ml. Intra- and inter-assay accuracies and precisions were within ±13.6% and ≤6.5%. The applicability of the assay was tested by analyzing dried blood spots samples of melanoma patients receiving vemurafenib. This assay met all predefined validation criteria and is considered suitable to quantify vemurafenib in dried blood samples.
    Bioanalysis 12/2014; 6(23):3215-24. DOI:10.4155/bio.14.171 · 3.03 Impact Factor
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    ABSTRACT: Background The aim of the current work was to perform a clinical trial simulation (CTS) analysis to optimize a drug-drug interaction (DDI) study of vincristine in children who also received azole antifungals, taking into account challenges of conducting clinical trials in this population, and, to provide a motivating example of the application of CTS in the design of pediatric oncology clinical trials.ProcedureA pharmacokinetic (PK) model for vincristine in children was used to simulate concentration-time profiles. A continuous model for body surface area versus age was defined based on pediatric growth curves. Informative sampling time windows were derived using D-optimal design. The CTS framework was used to different magnitudes of clearance inhibition (10%, 25%, or 40%), sample size (30–500), the impact of missing samples or sampling occasions, and the age distribution, on the power to detect a significant inhibition effect, and in addition, the relative estimation error (REE) of the interaction effect.ResultsA minimum group specific sample size of 38 patients with a total sample size of 150 patients was required to detect a clearance inhibition effect of 40% with 80% power, while in the case of a lower effect of clearance inhibition, a substantially larger sample size was required. However, for the majority of re-estimated drug effects, the inhibition effect could be estimated precisely (REE < 25%) in even smaller sample sizes and with lower effect sizes.Conclusion This work demonstrated the utility of CTS for the evaluation of PK clinical trial designs in the pediatric oncology population. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 12/2014; 61(12). DOI:10.1002/pbc.25198 · 2.56 Impact Factor
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    ABSTRACT: AimsPreviously published pharmacokinetic (PK) models for sunitinib and its active metabolite SU12662 were based on a limited dataset or lacked important elements such as correlations between sunitinib and its metabolite. The current study aimed to develop an improved PK model that circumvented these limitations and to prove the utility of the PK model in treatment optimization in clinical practice.Methods One thousand two hundred and five plasma samples from 70 cancer patients were collected from three PK studies with sunitinib and SU12662. A semi-physiological PK model for sunitinib and SU12662 was developed incorporating pre-systemic metabolism using non-linear mixed effects modelling (nonmem). Allometric scaling based on body weight was applied. The final model was used for simulation of the PK of different treatment regimens.ResultsSunitinib and SU12662 PK were best described by a one and two compartment model, respectively. Introduction of pre-systemic formation of SU12662 strongly improved model fit, compared with solely systemic metabolism. The clearance of sunitinib and SU12662 was estimated at 35.7 (relative standard error (RSE) 5.7%) l h−1 and 17.1 (RSE 7.4%) l h−1, respectively for 70 kg patients. Correlation coefficients were estimated between inter-individual variability of both clearances, both volumes of distribution and between clearance and volume of distribution of SU12662 as 0.53, 0.48 and 0.45, respectively. Simulation of the PK model predicted correctly the ratio of patients who did not reach proposed PK targets for efficacy.ConclusionsA semi-physiological PK model for sunitinib and SU12662 in cancer patients was presented including pre-systemic metabolism. The model was superior to previous PK models in many aspects.
    British Journal of Clinical Pharmacology 11/2014; 79(5). DOI:10.1111/bcp.12550 · 3.69 Impact Factor
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    ABSTRACT: Lenvatinib is an orally available multi-targeted tyrosine kinase inhibitor with anti-angiogenic and antitumor activity. To get more insight into the disposition of lenvatinib, a mass balance study was performed in patients with advanced solid tumors. A single oral 24 mg (100 μCi) dose of (14)C-lenvatinib was administered to six patients, followed by collection of blood, plasma, urine and feces for 7 to 10 days. The collected material was analyzed for total radioactivity, unchanged lenvatinib and selected metabolites. The safety and antitumor effect of a daily oral dose of 24 mg non-labeled lenvatinib were assessed in the extension phase of the study. Peak plasma concentrations of lenvatinib and total radioactivity were reached 1.6 and 1.4 h after administration, respectively, and their terminal phase half-lifes were 34.5 and 17.8 h, respectively. Unchanged lenvatinib systemic exposure accounted for 60 % of the total radioactivity in plasma. Peak concentrations of the analyzed metabolite were over 700-fold lower than the peak plasma concentration of lenvatinib. Ten days after the initial dose, the geometric mean (± CV) recovery of administered dose was 89 % ±10 %, with 64 % ±11 % recovered in feces and 25 % ±18 % in urine. Unchanged lenvatinib in urine and feces accounted for 2.5 % ±68 % of the administered dose, indicating a major role of metabolism in the elimination of lenvatinib. In conclusion, lenvatinib is rapidly absorbed and extensively metabolized, with subsequent excretion in urine and, more predominantly, in feces. Additionally, lenvatinib showed acceptable safety and preliminary antitumor activity.
    Investigational New Drugs 11/2014; 33(1). DOI:10.1007/s10637-014-0181-7 · 2.93 Impact Factor

Publication Stats

16k Citations
2,792.03 Total Impact Points


  • 1993–2015
    • Slotervaartziekenhuis
      Amsterdamo, North Holland, Netherlands
  • 1988–2015
    • Utrecht University
      • • Department of Pharmaceutical Sciences
      • • Faculty of Science
      • • Division of Toxicology
      • • Division of Biomedical Analysis
      Utrecht, Utrecht, Netherlands
  • 1988–2014
    • Netherlands Cancer Institute
      • • Department of Medical Oncology
      • • Department of Clinical Pharmacology
      • • Division of Experimental Therapy
      • • Division of Molecular Biology
      Amsterdamo, North Holland, Netherlands
  • 2013
    • Rijnstate Hospital
      Arnheim, Gelderland, Netherlands
  • 2011
    • VU University Medical Center
      • Department of Clinical Pharmacology and Pharmacy
      Amsterdamo, North Holland, Netherlands
  • 2007–2011
    • University Medical Center Utrecht
      Utrecht, Utrecht, Netherlands
    • University of Groningen
      Groningen, Groningen, Netherlands
    • Kantonsspital St. Gallen
      San Gallo, Saint Gallen, Switzerland
    • University of Florence
      Florens, Tuscany, Italy
  • 2010
    • Slotervaart Ziekenhuis Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 2008
    • Astellas Pharmaceutical
      Northbrook, Illinois, Japan
    • Atrium Medisch Centrum Parkstad
      Heerlen, Limburg, Netherlands
  • 2004–2007
    • VU University Amsterdam
      • Department of Clinical Chemistry
      Amsterdamo, North Holland, Netherlands
  • 2005
    • University of Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 2003
    • University of Crete
      • Department of Surgical Oncology
      Retimo, Crete, Greece
  • 2002
    • Pfizer Inc.
      New York, New York, United States
  • 2000
    • Boehringer Ingelheim
      Ingelheim-Mitte, Rheinland-Pfalz, Germany
  • 1998–2000
    • Leiden University
      Leyden, South Holland, Netherlands
    • Erasmus MC
      • Department of Internal Oncology
      Rotterdam, South Holland, Netherlands
  • 1996
    • Centro de Investigación del Cáncer
      Helmantica, Castille and León, Spain