Jan H M Schellens

Utrecht University, Utrecht, Utrecht, Netherlands

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Publications (792)3264.98 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
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    ABSTRACT: The fluoropyrimidines act by inhibiting thymidylate synthase (TS). Recent studies have shown that patients' risk of severe fluoropyrimidine-associated toxicity is affected by polymorphisms in the 5'-untranslated region of TYMS, the gene encoding TS. A G>C substitution in the promoter enhancer region of TYMS, rs183205964 (known as the 2RC allele), markedly reduces TS activity in vitro, but its clinical relevance is unknown. We determined rs183205964 in 1605 patients previously enrolled in a prospective multicenter study. Associations between putative low TS expression genotypes (3RC/2RC, 2RG/2RC, and 2RC/2RC) and severe toxicity were investigated using univariable and multivariable logistic regression. Activity of TS and TYMS gene expression were determined in peripheral blood mononuclear cells (PBMCs) of a patient carrying genotype 2RC/2RC and of a control group of healthy individuals. Among 1605 patients, 28 patients (1.7%) carried the 2RC allele. Twenty patients (1.2%) carried a risk-associated genotype (2RG/2RC, n=13; 3RC/2RC, n=6; and 2RC/2RC, n=1), the eight remaining patients had genotype 3RG/2RC. Early severe toxicity and toxicity-related hospitalization were significantly more frequent in risk-associated genotype carriers (OR 3.0, 95%CI 1.04-8.93, p=0.043 and OR 3.8, 95%CI 1.19-11.9, p=0.024, respectively, in multivariable analysis). The patient with genotype 2RC/2RC was hospitalized twice and had severe febrile neutropenia, diarrhea, and hand-foot syndrome. Baseline TS activity and gene expression in PBMCs of this patient, and a healthy individual with the 2RC allele, were found to be within the normal range. This study suggests that patients carrying rs183205964 are at strongly increased risk of severe, potentially life-threatening, toxicity when treated with fluoropyrimidines. This article is protected by copyright. All rights reserved. © 2015 UICC.
    International Journal of Cancer 07/2015; DOI:10.1002/ijc.29694 · 5.01 Impact Factor
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    ABSTRACT: Olaparib (AZD2281), a PARP-1/2 inhibitor, has been extensively investigated in clinical trials. However, limited clinical data are available about its long-term safety and anti-tumour activity. Patients had first participated in a phase I study of olaparib combined with carboplatin and/or paclitaxel. They continued with olaparib monotherapy in their best interest if they failed to tolerate the combination due to the treatment-related adverse events (TRAEs). Safety data were collected by physical examination and regular laboratory evaluations. Disease evaluations were performed by CT scan. At data cutoff, 21 patients were included; 10 with breast, 9 with ovarian and 2 with fallopian tube cancer of whom 16 patients had a BRCA mutation (13 BRCA1; 3 BRCA2). TRAEs were mostly haematological and most prominent shortly after switching from combination to monotherapy, probably due to carry-over effects of chemotherapy. Over time, both severity and frequency of TRAEs decreased. Responses to olaparib were durable with a median treatment duration of 52 (range 7-183) weeks. In total, nine (43%) patients were still on study at data cutoff. Continued long-term daily olaparib was found to be safe and tolerable. Encouragingly, patients who showed a favourable response on earlier combination therapy maintained this response on olaparib monotherapy.British Journal of Cancer advance online publication, 16 July 2015; doi:10.1038/bjc.2015.256 www.bjcancer.com.
    British Journal of Cancer 07/2015; DOI:10.1038/bjc.2015.256 · 4.82 Impact Factor
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    ABSTRACT: Phagocytes, the physiological compartment in which Leishmania parasites reside, are the main site of action of the drug miltefosine, but the intracellular pharmacokinetics of miltefosine remain unexplored. We developed a bioanalytical method to quantify miltefosine in human peripheral blood mononuclear cells (PBMCs), expanding from an existing high performance liquid chromatography-tandem mass spectrometry method for the quantification of miltefosine in plasma. The method introduced deuterated miltefosine as an internal standard. Miltefosine was extracted from PBMC pellets by addition of 62.5% methanol. Supernatant was collected, evaporated and reconstituted in plasma. Chromatographic separation was performed on a reversed phase C18 column and detection with a triple-quadrupole mass spectrometer. Miltefosine was quantified using plasma calibration standards ranging from 4 to 1000ng/mL. This method was validated with respect to its PBMC matrix effect, selectivity, recovery and stability. No matrix effect could be observed from the PBMC content (ranging from 0.17 to 26.3×10(6)PBMCs) reconstituted in plasma, as quality control samples were within 3.0% of the nominal concentration (precision less than 7.7%). At the lower limit of quantitation of 4 ng/mL plasma, corresponding to 0.12ng/10(6) PBMCs in a typical clinical sample, measured concentrations were within 8.6% of the nominal value. Recovery showed to be reproducible as adding additional pre-treatment steps did not increase the recovery with more than 9%. This method was successfully applied to measure intracellular miltefosine concentrations in PBMC samples from six cutaneous leishmaniasis patients up to one month post-treatment. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 06/2015; 998-999:57-62. DOI:10.1016/j.jchromb.2015.06.017 · 2.69 Impact Factor
  • Therapeutic drug monitoring 05/2015; DOI:10.1097/FTD.0000000000000224 · 1.93 Impact Factor
  • Cancer Research 05/2015; 75(9 Supplement):P6-16-04-P6-16-04. DOI:10.1158/1538-7445.SABCS14-P6-16-04 · 9.28 Impact Factor
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    ABSTRACT: Background AZD3514 is a first-in-class, orally bio-available, androgen-dependent and -independent androgen receptor inhibitor and selective androgen-receptor down-regulator (SARD). Methods In study 1 and 2, castration-resistant prostate cancer (CRPC) patients (pts) were initially recruited into a once daily (QD) oral schedule (A). In study 1, pharmacokinetic assessments led to twice daily (BID) dosing (schedule B) to increase exposure. Study 2 explored a once daily schedule. Results In study 1, 49 pts were treated with escalating doses of AZD3514 (A 35 pts, B 14 pts). Starting doses were 100 mg (A) and 1000 mg (B). The AZD3514 formulation was switched from capsules to tablets at 1000 mg QD. 2000 mg BID was considered non-tolerable due to grade (G) 2 toxicities (nausea [N], vomiting [V]). No adverse events (AEs) met the dose-limiting toxicity (DLT) definition. Thirteen pts received AZD3514 in study 2, with starting doses of 250 mg QD. The most frequent drug-related AEs were N: G1/2 in 55/70 pts (79 %); G3 in 1 pt (1.4 %); & V: G1/2 in 34/70 pts (49 %) & G3 in 1 pt (1.4 %). PSA declines (>/=50 %) were documented in 9/70 patients (13 %). Objective soft tissue responses per RECIST1.1 were observed in 4/24 (17 %) pts in study 1. Conclusion AZD3514 has moderate anti-tumour activity in pts with advanced CRPC but with significant levels of nausea and vomiting. However, anti-tumour activity as judged by significant PSA declines, objective responses and durable disease stabilisations, provides the rationale for future development of SARD compounds.
    Investigational New Drugs 04/2015; 33(3). DOI:10.1007/s10637-015-0235-5 · 2.93 Impact Factor
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    ABSTRACT: Human papillomavirus (HPV), p16 expression, and TP53 mutations are known prognostic factors in head and neck squamous cell carcinoma, but their role in squamous cell carcinoma of the anal canal (SCCAC) is less well established. The objective of this study was to determine the prognostic significance of tumour HPV status, p16 and p53 expression, and mutations in TP53 in patients with SCCAC receiving (chemo)radiotherapy. Human papillomavirus DNA was determined using an INNO-LiPA-based assay in tumour tissue of 107 patients with locally advanced SCCAC. Patients were treated with radiotherapy, with or without concurrent chemotherapy consisting of a fluoropyrimidine and mitomycin C. Expression of p16 and p53 was determined using immunohistochemistry. Exons 2-11 of TP53 in tumour tissue were sequenced. DNA of high-risk HPV types was detected in 93 out of 107 tumours (87%), all of which overexpressed p16 (HPV+/p16+). Of 14 HPV-negative (HPV-) tumours (13%), 10 (9%) were p16-negative (HPV-/p16-) and 4 (4%) overexpressed p16 (HPV-/p16+). Patients with HPV-/p16- disease had inferior 3-year locoregional control (LRC) (15%) compared with patients with HPV+/p16+ tumours (82%, P<0.001) and HPV-/p16+ tumours (75%, P=0.078). Similarly, 3-year overall survival (OS) was 35% (HPV-/p16-) vs 87% (HPV+/p16+, P<0.001) and 75% (HPV-/p16+, P=0.219). Disruptive mutations in TP53 were found in 80% of HPV-/p16- tumours vs 6% of HPV+/p16+ tumours (P<0.001). In multivariate analysis, HPV-/p16- status was an independent predictor of inferior LRC and OS. HPV- tumours are frequently TP53 mutated. HPV-/p16- status is a strong predictor for reduced LRC and OS, and alternative treatment strategies for patients with HPV-/p16- disease need to be explored.
    British Journal of Cancer 04/2015; 112(8):1358-1366. DOI:10.1038/bjc.2015.20 · 4.82 Impact Factor
  • N.G.L. Jager, S.C. Linn, J.H.M. Schellens, J.H. Beijnen
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    ABSTRACT: Tamoxifen, an endocrine agent, is widely used in the treatment of estrogen receptor-positive breast cancer. It has greatly reduced recurrence and mortality rates of breast cancer patients, however, not all patients benefit from tamoxifen treatment as in about 25-30% of the patients the disease recurs. Many researchers have sought to find factors associated with endocrine treatment outcome in the past years, however this quest has not been finished yet. In this paper, we focus on a factor that might influence outcome of tamoxifen treatment; inter-patient variability in tamoxifen pharmacokinetics. In recent years it has become clear that tamoxifen undergoes extensive metabolism and that some of the formed metabolites are much more pharmacologically active than tamoxifen itself. Despite the wide inter-patient variability in tamoxifen pharmacokinetics and pharmacodynamics, all patients receive a standard dose of 20 mg tamoxifen per day. Different approaches can be pursued to individualize tamoxifen dosing; genotyping, phenotyping and therapeutic drug monitoring. Therapeutic drug monitoring seems the most direct and promising approach, however, further clinical research is warranted to establish the added value of individual dosing in tamoxifen treatment optimization.
    Clinical Breast Cancer 04/2015; DOI:10.1016/j.clbc.2015.04.005 · 2.63 Impact Factor
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    ABSTRACT: The combination of an mTOR inhibitor with 5-fluorouracil-based anticancer therapy is attractive because of preclinical evidence of synergy between these drugs. According to our phase I study, the combination of capecitabine and everolimus is safe and feasible, with potential activity in pancreatic cancer patients. Patients with advanced adenocarcinoma of the pancreas were enrolled. Eligible patients had a WHO performance status 0-2 and adequate hepatic and renal functions. The treatment regimen consisted of capecitabine 1000 mg/m(2) BID day 1-14 and everolimus 10 mg daily (5 mg BID) in a continuous 21-day schedule. Tumor assessment was performed with CT-scan every three cycles. Primary endpoint was response rate (RR) according to RECIST 1.0. Secondary endpoints were progression-free survival, overall survival and 1-year survival rate. In total, 31 patients were enrolled. Median (range) treatment duration with everolimus was 76 days (1-431). Principal grade 3/4 toxicities were hyperglycemia (45 %), hand-foot syndrome (16 %), diarrhea (6 %) and mucositis (3 %). Prominent grade 1/2 toxicities were anemia (81 %), rash (65 %), mucositis (58 %) and fatigue (55 %). RR was 6 %. Ten patients (32 %) had stable disease resulting in a disease control rate of 38 %. Median overall survival was 8.9 months (95 % CI 4.6-13.1). Progression-free survival was 3.6 months (95 % CI 1.9-5.3). The oral regimen with the combination of capecitabine and everolimus is a moderately active treatment for patients with advanced pancreatic cancer, with an acceptable toxicity profile at the applied dose level.
    Cancer Chemotherapy and Pharmacology 03/2015; 75(6). DOI:10.1007/s00280-015-2730-y · 2.57 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: MET dysregulation occurs in multiple cancers, causing activation of the MET receptor tyrosine kinase. INC280 is an oral, highly selective MET inhibitor that has exhibited preclinical and preliminary clinical anti-tumor activity in various solid tumors. This dose escalation and expansion study was designed to evaluate INC280 safety and efficacy in patients (pts) with advanced MET-dependent solid tumors. The primary objectives of this Phase (Ph) I study were to determine the MTD or recommended Ph II dose (RP2D), and safety and tolerability of INC280. The secondary objectives were efficacy and PK assessment. Eligible pts (aged ≥18 years, PS ≤2) had tumors with high Met expression that were refractory to currently available therapies or for which no therapies existed. As of Sep 28, 2014, 91 pts were enrolled (median age 57 years, 70% male, 56% PS 0, 47% Asian): 38 in the dose escalation part and 53 in the dose expansion part. Pts were treated in 7 dose cohorts of 100-600 mg BID capsules or 400 mg BID tablets. DLTs occurred at 200, 250, and 450 (1 pt each) mg BID capsules and were Grade 3 fatigue (2 pts) and Grade 3 blood bilirubin increase (1 pt). The most frequent drug-related AEs (any grade) were nausea (33%), fatigue (25%), and vomiting (24%). The most common Grade 3/4 drug-related AEs were fatigue (4%) and increased lipase levels (3%) and occurred at 200 (1 pt), 250 (2 pts), 450 (1pt) and 600 (3 pts) mg BID capsules. RP2D was established at 600 mg BID capsules, but film-coated 400 mg INC280 tablets were developed and tested to improve pt convenience and compliance. INC280 400 mg BID tablets had comparable tolerability, safety profile and exposure compared with 600 mg BID capsules. The mean (CV%) steady state AUClast (Tlast ∼ 8h) and Cmax after 400 mg BID tablet vs 600 mg BID capsule were 24654 (33%, N = 4) vs 21249 (60%, N = 23) h*ng/mL and 7425 (30%, N = 4) vs 5240 (67%, N = 23) ng/mL respectively. Clinical activity was observed in advanced NSCLC patients, and updated efficacy data will be presented. Orally administered INC280 was well tolerated with a manageable safety profile. MTD was not reached, but the RP2D was established at 600 mg BID for capsules and 400 mg BID for tablets. Clinical trial identifier: NCT01324479. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
    Annals of Oncology 03/2015; 26(suppl 2):ii17. DOI:10.1093/annonc/mdv090.4 · 6.58 Impact Factor
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    ABSTRACT: This work was initiated to extend data on the effect of pharmacogenetics and chemotherapy pharmacokinetics (PK) on clinical outcome in patients with gastrointestinal malignancies. We assessed 44 gene polymorphisms in 16 genes (TYMS, MTHFR, GSTP1, GSTM1, GSTT1, DPYD, XRCC1, XRCC3, XPD, ERCC1, RECQ1, RAD54L, ABCB1, ABCC2, ABCG2 and UGT2B7) in 64 patients with metastatic colorectal cancer (CRC) receiving capecitabine/oxaliplatin and 76 patients with advanced gastroesophageal cancer (GEC) receiving epirubicin/cisplatin/capecitabine, respectively. Plasma concentrations of anticancer drugs were measured for up to 24 h, and results were submitted to population PK analysis. We calculated the association between gene polymorphisms, chemotherapy exposure, tumor response, progression-free survival (PFS), overall survival (OS) and chemotherapy-related toxicity using appropriate statistical tests. Patients with a low clearance of 5FU were at increased risk of neutropenia (P < 0.05) and hand-foot syndrome (P = 0.002). DPYD T85C, T1896C and A2846T mutant variants were associated with diarrhea (P < 0.05) and HFS (P < 0.02), and IVS14+1G>A additionally with diarrhea (P < 0.001). The TYMS 2R/3G, 3C/3G or 3G/3G promoter variants were associated with worse PFS in the CRC (HR = 2.0, P < 0.01) and GEC group (HR = 5.4, P < 0.001) and worse OS in the GEC group (HR = 4.7, P < 0.001). The GSTP1 A313G mutant variant was associated with a higher PFS (HR = 0.55, P = 0.001) and OS (HR = 0.60, P = 0.002) in the CRC group. Germline polymorphisms of DPYD, TYMS and GSTP1 have a significant effect on toxicity and clinical outcome in patients receiving capecitabine-based chemotherapy for advanced colorectal or gastroesophageal cancer. These data should further be validated in prospective clinical studies.
    Cancer Chemotherapy and Pharmacology 02/2015; 75(4). DOI:10.1007/s00280-015-2698-7 · 2.57 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: 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: - There is increasing discussion in the Netherlands about the introduction of a threshold value for the costs per extra year of life when reimbursing costs of new drugs. - The Medicines Committee ('Commissie Geneesmiddelen'), a division of the Netherlands National Healthcare Institute ('Zorginstituut Nederland'), advises on reimbursement of costs of new drugs. - This advice is based upon the determination of therapeutic value of the drug and the results of economic evaluations.- Mathematical models that predict future costs and effectiveness are often used in economic evaluations; these models can vary greatly in transparency and quality due to author assumptions.- Standardisation of cost-effectiveness models is one solution to overcome the unwanted variation in quality.- Discussions about the introduction of a threshold value can only be meaningful if all involved are adequately informed, and by high quality in cost-effectiveness research and, particularly, economic evaluations.- Collaboration and discussion between medical specialists, patients or patient organisations, health economists and policy makers, both in development of methods and in standardisation, are essential to improve the quality of decision making.
    Nederlands tijdschrift voor geneeskunde 01/2015; 159:A7728.
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    ABSTRACT: Currently, no country-specific metastatic breast cancer (MBC) observational costing data are available for the Netherlands and Belgium. Our aim is to describe country-specific resource use and costs of human epidermal receptor 2 (HER-2)-positive MBC in the Netherlands and Belgium, making use of real-world data.The eligibility period for patient selection was from April 2004 to April 2010. Inclusion and retrospective data collection begins at the time of first diagnosis of HER-2-positive MBC during the eligibility period and ends 24 months post-index diagnosis of MBC or at patient death.We identified 88 eligible patients in the Netherlands and 44 patients in Belgium. The total costs of medical treatment and other resource use utilisation per patient was €48 301 in the Netherlands and €37 431 in Belgium. Majority of costs was related to the use of trastuzumab in both countries, which was 50% of the total costs in the Netherlands and 56% in Belgium respectively.Our study provides estimates of resource use and costs for HER-2-positive MBC in the Netherlands and Belgium. We noticed various differences in resource use patterns between both countries demonstrating caution is needed when transferring cost estimates between countries.
    European Journal of Cancer Care 12/2014; 24(3). DOI:10.1111/ecc.12266 · 1.76 Impact Factor

Publication Stats

19k Citations
3,264.98 Total Impact Points


  • 2000–2015
    • Utrecht University
      • • Division of Pharmacoepidemiology and Pharmacotherapy
      • • Division of Biomedical Analysis
      • • Faculty of Science
      • • Department of Pharmaceutical Sciences
      • • Division of Toxicology
      Utrecht, Utrecht, Netherlands
  • 1995–2015
    • Netherlands Cancer Institute
      • • Division of Experimental Therapy
      • • Department of Clinical Pharmacology
      • • Department of Medical Oncology
      Amsterdamo, North Holland, Netherlands
  • 2013
    • Rijnstate Hospital
      Arnheim, Gelderland, Netherlands
  • 2012
    • Queen's University Belfast
      • Centre for Cancer Research and Cell Biology
      Béal Feirste, Northern Ireland, United Kingdom
    • Nederlands Jeugd Instituut
      Utrecht, Utrecht, Netherlands
  • 1994–2012
    • Slotervaartziekenhuis
      Amsterdamo, North Holland, Netherlands
  • 2011
    • University Medical Center Hamburg - Eppendorf
      • Department of Internal Medicine II. (Oncology/Haematologie with Sections Bone Marrow Transplantation and Pneumologie)
      Hamburg, Hamburg, Germany
  • 2010
    • Institute of Cancer Research
      Londinium, England, United Kingdom
  • 2009
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
  • 2007
    • University Medical Center Utrecht
      Utrecht, Utrecht, Netherlands
  • 2006–2007
    • University of Florence
      Florens, Tuscany, Italy
  • 2004–2007
    • VU University Amsterdam
      • Department of Clinical Chemistry
      Amsterdamo, North Holland, Netherlands
    • Fox Chase Cancer Center
      Filadelfia, Pennsylvania, United States
  • 2002–2007
    • Academisch Medisch Centrum Universiteit van Amsterdam
      Amsterdamo, North Holland, Netherlands
    • Pfizer Inc.
      New York, New York, United States
    • Institut de Cancérologie Gustave Roussy
      • Department of Radiotherapy
      Île-de-France, France
  • 2001–2007
    • Uppsala University
      • Department of Pharmacy
      Uppsala, Uppsala, Sweden
  • 2005
    • University of Amsterdam
      Amsterdamo, North Holland, Netherlands
    • Leiden University
      Leyden, South Holland, Netherlands
  • 2003
    • Nevada cancer institute
      Las Vegas, Nevada, United States
  • 1999–2003
    • Centro de Investigación del Cáncer
      Helmantica, Castille and León, Spain
    • Medisch Spectrum Twente
      Enschede, Overijssel, Netherlands
    • Bristol-Myers Squibb
      • Pharmaceutical Research Institute
      New York, New York, United States
  • 1999–2001
    • Institut Bergonié
      Burdeos, Aquitaine, France
  • 1996–1999
    • Erasmus MC
      • Department of Medical Oncology
      Rotterdam, South Holland, Netherlands