Jos H Beijnen

Netherlands Cancer Institute, Amsterdamo, North Holland, Netherlands

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Publications (701)2537.95 Total impact

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    ABSTRACT: Advances in genetic engineering have made it possible to generate human T cell products that carry desired functionalities, such as the ability to recognize cancer cells. The currently used strategies for the generation of gene-modified T cell products lead to highly differentiated cells within the infusion product, and on the basis of data obtained in preclinical models, this is likely to impact the efficacy of these products. We set out to develop a Good Manufacturing Practice (GMP) protocol that yields TCR gene modified T cells with more favourably properties for clinical application. Here, we show the robust clinical scale production of human peripheral blood T cells with an early memory phenotype that express a MART-1-specific T cell receptor. By combining selection and stimulation using anti-CD3/CD28 beads for retroviral transduction, followed by expansion in the presence of IL-7 and IL-15, production of a well-defined clinical scale TCR gene modified T cell product could be achieved. A major fraction of the T cells generated in this fashion were shown to co-express CD62L and CD45RA, and express CD27 and CD28 indicating a central memory or memory stem-like phenotype. Furthermore, these cells produced IFNγ, TNFα and IL-2, and displayed cytolytic activity against target cells expressing the relevant antigen. The T cell products manufactured by this robust and validated GMP production process are now undergoing testing in a phase I/IIa clinical trial in HLA-A*02:01 - MART-1 positive advanced stage melanoma patients. To our knowledge, this is the first clinical trial protocol in which the combination of IL-7 and IL-15 has been applied for the generation of gene-modified T cell products.
    Human Gene Therapy Methods 08/2014; · 4.02 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 08/2014; · 2.35 Impact Factor
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    ABSTRACT: BMS-275,183 is a novel oral C-4 methyl carbonate analogue of paclitaxel. Recently, a drug-drug interaction between BMS-275,183 and benzimidazole proton pump inhibitors (PPIs) was suggested in clinical trials resulting in elevated drug exposure and toxicity. We explored whether the interaction takes place at the level of P-glycoprotein (Pgp, MDR1, ABCB1), Breast Cancer Resistance Protein (BCRP, ABCG2) and MRP2 (ABCC2) using in vitro and in vivo models. In vitro cell survival, drug accumulation, efflux and transport studies with BMS-275,183 were performed employing MDCKII (wild-type, MDR1, BCRP, MRP2) and LLCPK (wild-type and MDR1) cells. In vivo the pharmacokinetics and tissue distribution of BMS-275,183 after p.o. and i.v. administration were explored in Mdr1a/1b(-/-) and wild-type mice, in presence or absence of the PPI pantoprazole. Results In vitro, BMS-275,183 was found to be a good substrate for MDR1, a moderate substrate for MRP2 and not a substrate for BCRP. In vivo, oral bioavailability, plasma AUC0-6h and brain concentrations were significantly 1.5-, 4-, and 2-fold increased, respectively, in Mdr1a/1b(-/-) compared with wild-type mice (p < 0.001). However, oral co-administration of pantoprazole (40 mg/kg) did not alter the pharmacokinetics of BMS-275,183 in wild-type mice. Conclusions BMS-275,183 is efficiently transported by Pgp and to a lesser extent by MRP2 in vitro. Genetic deletion of Pgp significantly altered the pharmacokinetics and brain distribution of p.o. and i.v. administered BMS-275,183 in Mdr1a/1b-/- compared to wild-type mice. Oral co-administration of BMS-275,183 with pantoprazole did not affect the pharmacokinetics of BMS-275,183 in wild-type mice, suggesting no interaction with PPI at the dose employed.
    Investigational New Drugs 07/2014; · 3.50 Impact Factor
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    ABSTRACT: Background: The recommended dose of vitamin D supplementation of 400 IU/day might be inadequate to treat obese children with vitamin D insufficiency. Therefore, we tested the efficacy and tolerability of a high loading dose vitamin D3 supplementation of 25,000 IU weekly in multiethnic obese children, 8-18 years of age, with vitamin D insufficiency/deficiency. Methods: Fasting blood samples were drawn for the assessment of vitamin D. Vitamin D-insufficient/-deficient children (<50 nmol/l) were supplemented, using a high loading dose of 25,000 IU weekly, and measured again 9 weeks later. Vitamin D supplementation was considered effective and tolerable when an increase to vitamin D sufficiency (25(OH)D >50 nmol/l) was reached in >75% without side effects nor reaching toxic levels. Results: In total, 109 children (mean ± SD age 11.1 ± 3.0, 34.2% boys, 90.8% obese) received vitamin D supplementation. In 84.4% of the children, the vitamin D status improved from insufficiency/deficiency (<50 nmol/l) to sufficiency (≥50 nmol/l). The majority of children that did not reach vitamin D sufficiency reported non-compliance. No side effects were reported, and the highest level reached was far below the threshold for toxicity. Conclusion: A high loading dose vitamin D3 supplementation is effective and well-tolerated in our cohort of multiethnic obese children with vitamin D insufficiency/deficiency. © 2014 S. Karger AG, Basel.
    Hormone Research in Paediatrics 07/2014; · 1.55 Impact Factor
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    ABSTRACT: Vitamin D insufficiency/deficiency is common among non-white children; however, little is known about the prevalence of vitamin D insufficiency/deficiency in non-white obese children living in the Netherlands. Therefore, a retrospective analysis was performed on data from multi-ethnic Dutch children and adolescents 6-18 years who visited the obesity outpatient clinic in 2012-2013. We performed anthropometric measurements, oral glucose tolerance test, and measured 25(OH)D and lipid levels. Vitamin D insufficiency was defined as 25(OH)D levels 37.5- <50 nmol/L and vitamin D deficiency as 25(OH)D <37.5 nmol/L. In total, data from 387 children were obtained (mean age 11.6 years, 41.1 % boys, 10.3 % Dutch native, 25.6 % Turkish, 24.5 % Moroccan, 7.5 % African Surinamese, and 7.0 % West African). The median 25(OH)D level was 34 (range 12-105) nmol/L. In total, 17.8 % were vitamin D sufficient, 24.5 % with vitamin D insufficiency, and 57.6 % with vitamin D deficiency. Obese ethnic children showed the highest (87.5 %) and normal weight white children showed the lowest (20.0 %) prevalence of vitamin D insufficiency/deficiency . Conclusion: Vitamin D insufficiency and deficiency is extremely prevalent in treatment-seeking obese ethnic children. However, there was no evidence of an effect of vitamin D status on various components of the metabolic syndrome in our cohort.
    European Journal of Pediatrics 07/2014; · 1.91 Impact Factor
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    ABSTRACT: Rucaparib is a potent, orally available, small-molecule inhibitor of poly ADP-ribose polymerase (PARP) 1 and 2. Ongoing clinical trials are assessing the efficacy of rucaparib alone or in combination with other cytotoxic drugs, mainly in breast and ovarian cancer patients with mutations in the breast cancer associated (BRCA) genes.
    Pharmaceutical research. 06/2014;
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    ABSTRACT: The anti-estrogenic effect of tamoxifen is suggested to be mainly attributable to its metabolite (Z)-endoxifen, and a minimum therapeutic threshold for (Z)-endoxifen in serum has been proposed. The objective of this research was to establish the relationship between dried blood spot (DBS) and serum concentrations of tamoxifen and (Z)-endoxifen to allow the use of DBS sampling, a simple and patient-friendly alternative to venous sampling, in clinical practice. Paired DBS and serum samples were obtained from 50 patients using tamoxifen and analyzed using HPLC-MS/MS. Serum concentrations were calculated from DBS concentrations using the formula calculated serum concentration = DBS concentration/([1-haematocrit (Hct)] + blood cell-to-serum ratio × Hct). The blood cell-to-serum ratio was determined ex vivo by incubating a batch of whole blood spiked with both analytes. The average Hct for female adults was imputed as a fixed value. Calculated and analyzed serum concentrations were compared using weighted Deming regression. Weighted Deming regression analysis comparing 44 matching pairs of DBS and serum samples showed a proportional bias for both analytes. Serum concentrations were calculated using [Tamoxifen] serum, calculated = [Tamoxifen] DBS /0.779 and [(Z)-Endoxifen] serum, calculated = [(Z)-Endoxifen] DBS /0.663. Calculated serum concentrations were within 20 % of analyzed serum concentrations in 84 and 100 % of patient samples for tamoxifen and (Z)-endoxifen, respectively. In conclusion, DBS concentrations of tamoxifen and (Z)-endoxifen were equal to serum concentrations after correction for Hct and blood cell-to-serum ratio. DBS sampling can be used in clinical practice.
    Breast Cancer Research and Treatment 05/2014; · 4.47 Impact Factor
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    ABSTRACT: Purpose Renal impairment (RI) studies are conducted to estimate the impact of RI on pharmacokinetics (PK). In some disease areas, these studies can be difficult to conduct, for instance due to the limited number of eligible patients. The objective of this analysis was to evaluate bias and precision of population PK parameters, and the dose adjustment error (DAE) for RI studies i) with different levels of study design imbalance in the stratification of subjects across RI categories, and ii) that include additional patients in the control arm of RI studies, that may be available from previously conducted PK studies. Methods Study designs were simulated and re-estimated using a hypothetical 2-compartmental PK model with varying magnitude of the fraction of renal elimination (FR) and magnitude of between-subject variability (BSV). The DAE was computed based on the difference between the theoretical necessary dose adjustment versus the empirical estimated dose adjustment to reach a similar exposure as controls. Results Although some design imbalance may still lead to DAEs of acceptable magnitude (DAE < -11.05-14.44 inter-quartile range, IQR), at least some patients are necessary in the more severe RI groups. When 100 additional patients with normal renal function were included in a sub-informative design, the DAE changed from < -7.63-16.64 IQR to < -8.89-8.69 IQR. Conclusions We quantified the impact of study design imbalance on bias and precision of PK parameters and DAE, as may occur for RI studies in some indications. Adding additional data from earlier studies to the analysis dataset improves the bias and precision of PK parameters.
    Investigational New Drugs 05/2014; · 3.50 Impact Factor
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    ABSTRACT: Objectives The aim of this study is to establish the inhibitory effects of 14 commonly used complementary and alternative medicines (CAM) on the metabolism of cytochrome P450 2C9 (CYP2C9) substrates 7-methoxy-4-trifluoromethyl coumarine (MFC) and tolbutamide. CYP2C9 is important for the metabolism of numerous drugs and inhibition of this enzyme by CAM could result in elevated plasma levels of drugs that are CYP2C9 substrates. Especially for anticancer drugs, which have a narrow therapeutic window, small changes in their plasma levels could easily result in clinically relevant toxicities.Methods The effects of CAM on CYP2C9-mediated metabolism of MFC were assessed in Supersomes, using the fluorometric CYP2C9 inhibition assay. In human liver microsomes (HLM) the inhibition of CYP2C9-mediated metabolism of tolbutamide was determined, using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS).Key findingsThe results indicated milk thistle as the most potent CYP2C9 inhibitor. For milk thistle, silybin (main constituent of milk thistle) was mainly responsible for the inhibition of CY2C9.Conclusions Milk thistle and green tea were confirmed as potent inhibitors of CYP2C9-mediated metabolism of multiple substrates in vitro. Clinical studies with milk thistle are recommended to establish the clinical relevance of the demonstrated CYP2C9 inhibition.
    Journal of Pharmacy and Pharmacology. 05/2014;
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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 05/2014; · 6.20 Impact Factor
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    ABSTRACT: To clarify the role of ABCB1, ABCG2, and CYP3A in blood and brain exposure of everolimus using knockout mouse models. We used wild-type, Abcb1a/1b(-/-), Abcg2(-/-), Abcb1a/1b;Abcg2(-/-) and Cyp3a(-/-) mice to study everolimus oral bioavailability and brain accumulation. Following everolimus administration, brain concentrations and brain-to-liver ratios were substantially increased in Abcb1a/1b(-/-) and Abcb1a/1b;Abcg2(-/-), but not Abcg2(-/-) mice. The fraction of everolimus located in the plasma compartment was highly increased in all knockout strains. In vitro, everolimus was rapidly degraded in wild-type but not knockout plasma. Carboxylesterase 1c (Ces1c), a plasma carboxylesterase gene, was highly upregulated (~80-fold) in the liver of knockout mice relative to wild-type mice, and plasma Ces1c likely protected everolimus from degradation by binding and stabilizing it. This binding was prevented by preincubation with the carboxylesterase inhibitor BNPP. In vivo knockdown experiments confirmed the involvement of Ces1c in everolimus stabilization. Everolimus also markedly inhibited the hydrolysis of irinotecan and p-nitrophenyl acetate by mouse plasma carboxylesterase and recombinant human CES2, respectively. After correcting for carboxylesterase binding, Cyp3a(-/-), but not Abcb1a/1b(-/-), Abcg2(-/-), or Abcb1a/1b;Abcg2(-/-) mice, displayed highly (>5-fold) increased oral availability of everolimus. Brain accumulation of everolimus was restricted by Abcb1, but not Abcg2, suggesting the use of coadministered ABCB1 inhibitors to improve brain tumor treatment. Cyp3a, but not Abcb1a/1b, restricted everolimus oral availability, underscoring drug-drug interaction risks via CYP3A. Upregulated Ces1c likely mediated the tight binding and stabilization of everolimus, causing higher plasma retention in knockout strains. This Ces upregulation might confound other pharmacological studies.
    Clinical Cancer Research 04/2014; · 7.84 Impact Factor
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    ABSTRACT: Tamoxifen is considered a pro-drug of its active metabolite endoxifen. The major metabolic enzymes involved in endoxifen formation are CYP2D6 and CYP3A. There is considerable evidence that variability in activity of these enzymes influences endoxifen exposure and thereby may influence clinical outcome of tamoxifen treatment. We aimed to quantify the impact of metabolic phenotype on the pharmacokinetics of tamoxifen and endoxifen. We assessed the CYP2D6 and CYP3A metabolic phenotypes in 40 breast cancer patients on tamoxifen treatment with a single dose of dextromethorphan as a dual phenotypic probe for CYP2D6 and CYP3A. The pharmacokinetics of dextromethorphan, tamoxifen and their relevant metabolites were analyzed using non-linear mixed effects modeling. Population pharmacokinetic models were developed for dextromethorphan, tamoxifen and their metabolites. In the final model for tamoxifen, the dextromethorphan derived metabolic phenotypes for CYP2D6 as well as CYP3A significantly (p<0.0001) explained 54% of the observed variability in endoxifen formation (inter-individual variability reduced from 55% to 25%). We have shown that not only CYP2D6, but also CYP3A enzyme activity influences the tamoxifen to endoxifen conversion in breast cancer patients. Our developed model may be used to separately assess the impact of CYP2D6 and CYP3A mediated drug-drug interactions with tamoxifen without the necessity of administering this anti-estrogenic drug and to support Bayesian guided therapeutic drug monitoring of tamoxifen in routine clinical practice.
    British Journal of Clinical Pharmacology 04/2014; · 3.58 Impact Factor
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    ABSTRACT: An intoxication with drugs, ethanol or cleaning solvents may cause a complex clinical scenario if multiple agents have been ingested simultaneously. The situation can become even more complex in patients with (multiple) co-morbidities. A 59-year-old male with type 2 diabetes mellitus (without treatment two weeks before the intoxication) intentionally ingested a substantial amount of ethanol along with ~750 mL of laminate floor cleaner containing citric acid. The patient was admitted with severe metabolic acidosis (both ketoacidosis and lactic acidosis, with serum lactate levels of 22 mmol/L). He was treated with sodium bicarbonate, insulin and thiamine after which he recovered within two days. Diabetic ketoacidosis and lactic acidosis aggravated due to ethanol intoxication, thiamine deficiency and citrate. The high lactate levels were explained by excessive lactate formation caused by the combination of untreated diabetes mellitus, thiamine deficiency and ethanol abuse. Metabolic acidosis in diabetes is multifactorial, and the clinical situation may be further complicated, when ingestion of ethanol and toxic agents are involved. Here, we reported a patient in which diabetic ketoacidosis was accompanied by severe lactic acidosis as a result of citric acid and mainly ethanol ingestion and a possible thiamine deficiency. In the presence of lactic acidosis in diabetic ketoacidosis, physicians need to consider thiamine deficiency and ingestion of ethanol or other toxins.This article is protected by copyright. All rights reserved.
    Basic & Clinical Pharmacology & Toxicology 04/2014; · 2.18 Impact Factor
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    ABSTRACT: Little is known about the optimal clinical use of ABT-888 (veliparib) for treatment of glioblastoma. ABT-888 is a PARP inhibitor undergoing extensive clinical evaluation in glioblastoma, because it may synergize with the standard-of-care temozolomide (TMZ). We have elucidated important factors controlling ABT-888 efficacy in glioblastoma. Experimental design: We used genetically engineered spontaneous glioblastoma mouse models and allograft models that were orthotopically transplanted into wildtype (WT) and Abcb1/Abcg2 deficient (KO) recipients. ABT-888/TMZ is not efficacious against p53;p16Ink4a/p19Arf;K Rasv12;LucR allografts in WT recipients, indicating inherent resistance. Abcb1/Abcg2 mediated efflux of ABT-888 at the blood-brain barrier (BBB) causes a 5-fold reduction of ABT-888 brain penetration (p<0.0001) that was fully reversible by elacridar. Efficacy studies in WT and KO recipients and/or concomitant elacridar demonstrate that Abcb1/Abcg2 at the BBB and in tumor cells impair TMZ/ABT-888 combination treatment efficacy. Elacridar also markedly improved TMZ/ABT-888 combination treatment in the spontaneous p53;p16Ink4a/p19Arf;K-Rasv12;LucR glioblastoma model. Importantly, ABT-888 does enhance TMZ efficacy in Pten deficient glioblastoma allografts and spontaneous tumors, even in Abcb1/Abcg2 proficient WT mice. Loss of PTEN occurs frequently in glioblastoma (36%) and in silico analysis on glioblastoma patient samples revealed that it is associated with a worse overall survival (310 days vs. 620 days, n=117). The potential of ABT-888 in glioblastoma can best be demonstrated in patients with PTEN null tumors. Therefore, clinical trials with ABT-888 should evaluate these patients as a separate group. Importantly, inhibition of ABCB1 and ABCG2 (by elacridar) may improve the efficacy of TMZ/ABT-888 therapy in all glioblastoma patients.
    Clinical Cancer Research 03/2014; · 7.84 Impact Factor
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    ABSTRACT: Paclitaxel and docetaxel are active against a range of human cancers. Their antitumor activity is based on stabilization of the microtubule dynamics and thereby disruption of the cell cycle. The taxanes are administered as intravenous solutions in a short administration schedule. Distribution of both taxanes is rapid, with large volumes of distribution and significant binding to plasma proteins. The metabolism of paclitaxel is mediated primarily by the P450 cytochrome enzymes CYP2C8 and CYP3A, whereas docetaxel is only metabolized by CYP3A4. The most common toxicities after intravenous administration are neutropenia, hypersensitivity reactions, neurotoxicity, and alopecia. Several new administration forms are in development; albumin-bound paclitaxel (Abraxane) has recently been registered. Oral formulations of taxanes have been developed, and several are now undergoing phase I trials. New formulations might improve efficacy and safety and could be easier to use.
    Anti-cancer drugs 03/2014; · 2.23 Impact Factor
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    ABSTRACT: Regorafenib has recently been approved for the treatment of colorectal cancer. A bioanalytical liquid chromatography-tandem mass spectrometric assay for this multikinase inhibitor was developed and validated in plasma. The concentration range of the assay was 25-25,000 ng/mL. Protein precipitation with acetonitrile was used as sample pre-treatment with sorafenib as internal standard. The extract was diluted with methanol (25%, v/v) and then injected onto the sub-2 µm particle, bridged ethylsilicia hybrid trifunctional bonded C18 column. Isocratic elution using 0.02% (v/v) formic acid in a methanol-water mixture was used. Compounds were monitored by a triple quadrupole mass spectrometer in the selected reaction monitoring mode after positive electrospray ionization. Double logarithmic calibration was used; within-day precisions, between-day precisions, and accuracies were 3.2-9.2, 4.1-12.3 and 94.8-103.0%, respectively. High drug stability was observed under all relevant storage conditions. The assay was used to measure drug concentrations in a pharmacokinetic study in wild-type FVB mice. Copyright © 2014 John Wiley & Sons, Ltd.
    Biomedical Chromatography 03/2014; · 1.95 Impact Factor
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    ABSTRACT: There is accumulating evidence for potential benefits of therapeutic drug monitoring (TDM) in the treatment of cancer with tyrosine kinase inhibitors (TKIs). Relationships between exposure and response (efficacy/toxicity) have been established for several TKIs. For example, the pharmacokinetic targets for efficacy of imatinib, sunitinib and pazopanib have been defined as trough plasma concentrations (C trough) of >1,000, >50 and >20,000 ng/mL for selected indications, respectively. Dose adjustment based on pharmacokinetic targets could therefore increase response rates and duration. Furthermore, with appropriate target concentrations defined, excessive side effects in patients using the current fixed dosing strategy may be prevented. This review provides a practical guideline for TDM for the currently approved TKIs at 28 February 2013. The focus of this article is on the elaboration of exposure and response relationships of TKIs with proposed pharmacokinetic targets, mainly C trough, and further on the interpretation of the pharmacokinetic targets with recommendations for dose titrations.
    Clinical Pharmacokinetics 02/2014; · 5.49 Impact Factor
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    ABSTRACT: The radical change of lifestyle during Ramadan fast has shown to affect cardiometabolic risk variables in adults. In youth, however, no studies are available. We aimed to evaluate the effect of Ramadan fast on Body Mass Index (BMI) and the cardiometabolic profile of obese adolescents. A prospective cohort study was conducted. We measured weight, height, body composition, blood pressure, heart rate, glucose, insulin, total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol, triglycerides, and high sensitivity C-reactive protein (hs-CRP) levels before, during the last week of and at 6 weeks after Ramadan. Twenty-five obese adolescents were included. BMI and glucose metabolism did not change after Ramadan or at 6 week after cessation of Ramadan. At the end of Ramadan, a significant decrease in body fat percentage was observed, while significant increases in heart rate, total cholesterol, LDL cholesterol, HDL cholesterol, and hs-CRP were found (all P < 0.05). Six weeks after Ramadan, all parameters returned to baseline levels. Conclusion: In this sample of 25 ethnic obese adolescents transient cardiometabolic changes were observed during Ramadan fasting. Since most of these changes were reversible within 6 weeks, there seems no harm or benefit for obese adolescents to participate in Ramadan.
    European Journal of Pediatrics 02/2014; · 1.91 Impact Factor
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    ABSTRACT: A flexed posture (FP) is characterized by protrusion of the head and an increased thoracic kyphosis (TK), which may be caused by osteoporotic vertebral fractures (VFs). These impairments may affect motor function, and consequently increase the risk of falling and fractures. The aim of the current study was therefore to examine postural control during walking in elderly patients with FP, and to investigate the relationship with geriatric phenomena that may cause FP, such as increased TK, VFs, frailty, polypharmacy and cognitive impairments. Fifty-six elderly patients (aged 80±5.2 years; 70% female) walked 160m at self-selected speed while trunk accelerations were recorded. Walking speed, mean stride time and coefficient of variation (CV) of stride time were recorded. In addition, postural control during walking was quantified by time-dependent variability measures derived from the theory of stochastic dynamics, indicating smoothness, degree of predictability, and local stability of trunk acceleration patterns. Twenty-five patients (45%) had FP and demonstrated a more variable and less structured gait pattern, and a more irregular trunk acceleration pattern than patients with normal posture. FP was significantly associated with an increased TK, but not with other geriatric phenomena. An increased TK may bring the body's centre of mass forward, which requires correcting responses, and reduces the ability to respond on perturbation, which was reflected by higher variation in the gait pattern in FP-patients. Impairments in postural control during walking are a major risk factor for falling: the results indicate that patients with FP have impaired postural control during walking and might therefore be at increased risk of falling.
    Gait & posture 02/2014; 39(2):767-772. · 2.58 Impact Factor

Publication Stats

11k Citations
2,537.95 Total Impact Points


  • 1991–2014
    • Netherlands Cancer Institute
      • • Division of Molecular Pathology
      • • Department of Clinical Pharmacology
      • • Division of Molecular Biology
      • • Division of Experimental Therapy
      • • Center for Biomedical Genetics
      • • Department of Medical Oncology
      Amsterdamo, North Holland, Netherlands
    • Kumamoto University
      • Department of Physical Pharmaceutics
      Kumamoto, Kumamoto Prefecture, Japan
  • 1990–2014
    • Slotervaartziekenhuis
      Amsterdamo, North Holland, Netherlands
  • 1985–2014
    • Utrecht University
      • • Department of Pharmaceutical Sciences
      • • Division of Biomedical Analysis
      • • Division of Veterinary Pharmaceuticals, Pharmacology and Toxicology
      Utrecht, Utrecht, Netherlands
  • 2013
    • Rijnstate Hospital
      Arnheim, Gelderland, Netherlands
  • 2011–2013
    • University of Amsterdam
      • Faculty of Medicine AMC
      Amsterdamo, North Holland, Netherlands
  • 2006–2013
    • Slotervaart Ziekenhuis Amsterdam
      • Department of Geriatric Medicine
      Amsterdamo, North Holland, Netherlands
    • Medicines Evaluation Board, Netherlands
      Utrecht, Utrecht, Netherlands
  • 2009–2012
    • University Medical Center Utrecht
      • Julius Center for Health Sciences and Primary Care
      Utrecht, Utrecht, Netherlands
  • 2001–2012
    • Uppsala University
      • Department of Pharmacy
      Uppsala, Uppsala, Sweden
  • 2007–2011
    • Kantonsspital St. Gallen
      San Gallo, Saint Gallen, Switzerland
    • Insitute de Cancérologie de l'Ouest - Centre René Gauducheau
      Naoned, Pays de la Loire, France
  • 2006–2010
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • Department of Medical Oncology
      Amsterdam, North Holland, Netherlands
  • 2008–2009
    • Astellas Pharmaceutical
      Northbrook, Illinois, Japan
    • Atrium Medisch Centrum Parkstad
      Heerlen, Limburg, Netherlands
  • 2004–2009
    • VU University Medical Center
      • Department of Internal Medicine
      Amsterdamo, North Holland, Netherlands
  • 2003–2008
    • University of Crete
      • Department of Surgical Oncology
      Retimo, Crete, Greece
  • 2002–2004
    • Wyeth
      New Johnsonville, Tennessee, United States
  • 1995
    • Radboud University Medical Centre (Radboudumc)
      Nymegen, Gelderland, Netherlands