Teun van Gelder

Erasmus MC, Rotterdam, South Holland, Netherlands

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Publications (330)1406.68 Total impact

  • Patient Education and Counseling 11/2015; DOI:10.1016/j.pec.2015.11.018 · 2.20 Impact Factor
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    ABSTRACT: In association with therapeutic drug monitoring (TDM) of immunosuppressive drugs, pharmacogenetics has rapidly emerged as an additional tool to refine dose selection or, more interestingly to select, a priori, the first dose to administer. Pharmacogenetic biomarkers are now readily available in most transplantation centers, at a limited cost and within a limited analytical time frame, which make them compatible with the clinical decision process. However, despite some evidence of clear associations between polymorphisms in genes encoding metabolizing enzymes (CYP3A4/3A5, UGT1A9) or drug transporters (ABCB1, ABCC2, SLCO1B1) and pharmacokinetics of several immunosuppressive drugs, pre-emptive genotyping and selection of the optimal starting dose based on the genetic background of the patient is still rarely performed in clinical practice. The main reason is probably the lack of formal proof that clinical outcome really improves following genotype-based dosing. So far, the only clinical recommendation in relation to pharmacogenetic biomarkers should be a doubling of the starting Tacrolimus (Tac) dose in patients who are CYP3A5 expressers, and even in this case, some authors still do not recommend pre-emptive genotyping but only genotype-based adaptation if the CYP3A5 genotype is already known. However, with the rise of new technologies, as next generation sequencing, allowing to obtain pre-emptive genetic information, one must be aware that the question will no longer be whether to genotype or not, but rather whether or not to use the information already there. There was therefore a need to update the information available in relation to pharmacogenetic biomarkers for calcineurin inhibitors (CNIs), mycophenolic acid (MPA) and mammalian target of rapamycin inhibitors (mTORi).
    Therapeutic drug monitoring 10/2015; DOI:10.1097/FTD.0000000000000255 · 2.38 Impact Factor
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    ABSTRACT: Background and objective: The anti-oestrogen tamoxifen requires metabolic activation to endoxifen by cytochrome P450 (CYP) enzymes, predominantly CYP2D6. Potent CYP2D6-inhibiting antidepressants can seriously disrupt tamoxifen metabolism, probably influencing the efficacy of tamoxifen. For this reason, paroxetine and fluoxetine are recommended not to be used with tamoxifen in breast cancer patients. We investigated the effects of switching potent CYP2D6-inhibiting antidepressants to weak CYP2D6-inhibiting antidepressants on the plasma pharmacokinetics of tamoxifen. Methods: Ten breast cancer patients who were treated with tamoxifen in combination with a potent CYP2D6-inhibiting antidepressant (paroxetine or fluoxetine) for at least 4 weeks were enrolled. Under close supervision by a psychiatrist, patients were switched to treatment with escitalopram or venlafaxine (weak CYP2D6-inhibiting antidepressants). Before and after the switch, pharmacokinetic blood sampling was performed over 24 h. Pharmacokinetic parameters were estimated using noncompartmental analysis. Adverse effects were recorded during the study. Results: Endoxifen exposure was ~3-fold higher during escitalopram co-administration than during paroxetine or fluoxetine co-administration (median 387 nM·h [range 159-637 nM·h] versus 99.2 nM·h [range 70.0-210 nM·h]; P = 0.012; Wilcoxon signed-rank test). The ratio of endoxifen to N-desmethyltamoxifen and the ratio of 4-hydroxytamoxifen to tamoxifen increased by 3.3- and ~1.5-fold, reflecting increased CYP2D6 activity. Antidepressant switching did not result in psychiatric problems or antidepressant-related adverse effects. Conclusion: In this study, switching to the weak CYP2D6 inhibitor escitalopram was safe and feasible and resulted in clinically relevant rises in endoxifen concentrations. We therefore advise switching paroxetine and fluoxetine to escitalopram in patients using tamoxifen. However, switching should always be weighed in individual patients.
    Clinical Pharmacokinetics 10/2015; DOI:10.1007/s40262-015-0315-x · 5.05 Impact Factor
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    ABSTRACT: Background and objectives: Definition of individual risk profile is the first step to implement strategies to keep the delicate balance between under- and overimmunosuppression after kidney transplantation. Design, setting, participants, & measurements: We used data from the Efficacy Limiting Toxicity Elimination Symphony Study (1190 patients between 2002 and 2004) to model risk of rejection and infection in the first year after kidney transplantation. External validation was performed in a study population from the Fixed-Dose Concentration-Controlled Trial (630 patients between 2003 and 2006). Results: Despite different temporal dynamics, rejections and severe infections had similar overall incidences in the first year after transplantation (23.4% and 25.5%, respectively), and infections were the principal cause of death (43.2% of all deaths). Recipient older age, deceased donor, higher number of HLA mismatches, and high risk for cytomegalovirus disease were associated with infection; deceased donor, higher number of HLA mismatches, and immunosuppressive therapy including cyclosporin A (compared with tacrolimus), with rejection. These factors were integrated into a two-dimensional risk stratification model, which defined four risk groups: low risk for infection and rejection (30.8%), isolated risk for rejection (36.1%), isolated risk for infection (7.0%), and high risk for infection and rejection (26.1%). In internal validation, this model significantly discriminated the subgroups in terms of composite end point (low risk for infection/rejection, 24.4%; isolated risk for rejection and isolated risk for infection, 31.3%; high risk for infection/rejection, 54.4%; P<0.001), rejection episodes (isolated risk for infection and low risk for infection/rejection, 13.0%; isolated risk for rejection and high risk for infection/rejection, 24.2%; P=0.001), and infection episodes (low risk for infection/rejection and isolated risk for rejection, 12.0%; isolated risk for infection and high risk for infection/rejection, 37.6%; P<0.001). External validation confirmed the applicability of the model to an independent cohort. Conclusions: We propose a two-dimensional risk stratification model able to disentangle the individual risk for rejection and infection in the first year after kidney transplantation. This concept can be applied to implement a personalized immunosuppressive and antimicrobial treatment approach.
    Clinical Journal of the American Society of Nephrology 10/2015; DOI:10.2215/CJN.01790215 · 4.61 Impact Factor
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    ABSTRACT: Background: Low-molecular-weight heparins (LMWHs) have been shown to accumulate in patients with renal insufficiency, especially in therapeutic dosages. Although no appropriate studies have been conducted for prophylactic dosages of nadroparin, dose reduction is sometimes recommended, especially for high prophylactic dosages. We assessed accumulation of a prophylactic dose of 5700 IU subcutaneous nadroparin once daily in patients with renal insufficiency. Methods: We conducted a prospective cohort study and measured peak anti-Xa activity four hours after subcutaneous nadroparin injection on day 1, 3, 5 and if possible day 10 in adults with and without renal insufficiency defined as a glomerular filtration rate (GFR) below or above 50 ml/min/1.73 m2. Patients with a GFR below 10 ml/min/1.73 m2 were excluded. Results: We included 14 patients in each group. In the group with renal failure 12 patients had a GFR between 30 and 50 ml/min/1.73 m2. Peak anti-Xa activity showed a high interindividual variability, but was fairly constant within each patient. There was no rise in peak anti-Xa activity on day 3 and 5 after consecutive administration. In the group with normal renal function, peak anti-Xa activity declined on day 5 compared with day 1 (p = 0.005). Conclusion: Prophylactic dosages of nadroparin showed no accumulation in patients with a GFR between 30-50 ml/ min/1.73 m2. Dose reduction in this group could lead to suboptimal thromboprophylaxis. Due to underrepresentation of patients with a GFR < 30 ml/min/1.73 m2 (n = 2), we cannot give recommendations for this group.
  • Eric C. T. Geijteman · Henning Tiemeier · Teun van Gelder ·

    JAMA Internal Medicine 10/2015; 175(10):1724. DOI:10.1001/jamainternmed.2015.3997 · 13.12 Impact Factor
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    ABSTRACT: Anti-tumor necrosis factor alpha (TNFα) therapy is effective in pediatric patients with inflammatory bowel disease (IBD) but associated with a risk of developing anti-drug antibodies (ADA) which lower the efficacy. Incorporating measurement of trough levels and ADA (therapeutic drug monitoring) may prevent the development of neutralizing ADA or could contribute to more optimal treatment strategies if ADA are already formed. The aim of this review was to investigate the role of therapeutic drug monitoring in children and adolescents with IBD exposed to anti-TNFα agents. A literature search identified publications that measured anti-TNFα drug trough levels and/or ADA in children or adolescents with IBD. Studies were eligible when (1) article was written in English, (2) original data were available, (3) full text article or abstract was available, (4) measurement of antibodies against anti-TNFα drugs or trough level of anti-TNFα drugs were reported, and (5) levels were measured in pediatric patients with IBD. The search yielded 811 articles, of which 795 articles were excluded based on title or abstract. A total of 14 studies were included in the review. Therapeutic drug monitoring within the pediatric IBD population certainly has a potential benefit. As occurrence of immune reactions to anti-TNFα agents varies widely, incorporating measurement of IFX trough levels at week 8 or week 14 predicts therapy response and allows for dose adjustments to reach therapeutic drug concentrations. However, a clinically relevant cutoff level for ADA has not been defined yet, and the optimal intervention strategy still has to be determined.
    Inflammatory Bowel Diseases 09/2015; 21(9):2214-2221. DOI:10.1097/MIB.0000000000000420 · 4.46 Impact Factor
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    ABSTRACT: Background The antipsychotics risperidone, aripiprazole and pipamperone are frequently prescribed for the treatment in children with autism. The aim of this study was to validate an ultra-high performance liquid chromatography-mass spectrometry method for the quantification of these antipsychotics in plasma.Methods An ultra-high performance liquid chromatography-mass spectrometry assay was developed for the determination of the drugs and metabolites. Gradient elution was performed on a reversed phase column with a mobile phase consisting of ammonium acetate, formic acid in methanol or in Milli-Q ultrapure water at a flow rate of 0.5 mL/min.ResultsThe method was validated according to the FDA guidelines. The analytes were found stable enough after reconstitution and injection of only 5 μL improved the accuracy and precision in combination with the internal standard. Calibration curves of all five analytes were linear. All analytes were stable for at least 72 h in the auto-sampler and the QC high of 9-OH-risperidone was stable for 48 h.Conclusions The method allows quantification of all analytes. The advantage of this method is the combination of a minimal injection volume, a short run-time, an easy sample preparation method and the ability to quantify all analytes in one run. This article is protected by copyright. All rights reserved.
    Biomedical Chromatography 09/2015; DOI:10.1002/bmc.3610 · 1.72 Impact Factor
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    Intensive Care Medicine 08/2015; 41(11). DOI:10.1007/s00134-015-4002-z · 7.21 Impact Factor

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    ABSTRACT: Although therapeutic dosages of most low-molecular-weight heparins (LMWHs) are known to accumulate in patients with renal insufficiency, for the lower prophylactic dosages this has not been clearly proven. Nevertheless, dose reduction is often recommended. We conducted a systematic review to investigate whether prophylactic dosages of LMWH accumulate in renal insufficient patients. A comprehensive search was conducted on 17 February 2015 using Embase, Medline, Web of Science, Scopus, Cochrane, PubMed publisher, and Google scholar. The syntax emphasized for LMWHs, impaired renal function, and pharmacokinetics. The search yielded 674 publications. After exclusion by reading the titles, abstracts, and if necessary the full paper, 11 publications remained. For dalteparin and tinzaparin, no accumulation was observed. Enoxaparin, on the other hand, did lead to accumulation in patients with renal insufficiency, although not in patients undergoing renal replacement therapy. Bemiparin and certoparin also did show accumulation. No data were available for nadroparin. In this systematic review, we show that prophylactic dosages of tinzaparin and dalteparin are likely to be safe in patients with renal insufficiency and do not need dose reduction based on the absence of accumulation. However, prophylactic dosages of enoxaparin, bemiparin, and certoparin did show accumulation in patients with a creatinine clearance (CrCl) below 30 ml/min, and therefore, dose reduction is required. The differences in occurrence of accumulation seem to depend on the mean molecular weight of LMWHs.
    European Journal of Clinical Pharmacology 06/2015; 71(8). DOI:10.1007/s00228-015-1880-5 · 2.97 Impact Factor
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    ABSTRACT: The anti-estrogen tamoxifen is characterized by a large variability in response, partly due to pharmacokinetic differences. We examined circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients. Pharmacokinetic analysis was performed in mice, dosed at six different times (24-h period). Tissue samples were used for mRNA expression analysis of drug-metabolizing enzymes. In patients, a cross-over study was performed. During three 24-h periods, after tamoxifen dosing at 8 a.m., 1 p.m., and 8 p.m., for at least 4 weeks, blood samples were collected for pharmacokinetic measurements. Differences in tamoxifen pharmacokinetics between administration times were assessed. The mRNA expression of drug-metabolizing enzymes showed circadian variation in mouse tissues. Tamoxifen exposure seemed to be highest after administration at midnight. In humans, marginal differences were observed in pharmacokinetic parameters between morning and evening administration. Tamoxifen C max and area under the curve (AUC)0-8 h were 20 % higher (P < 0.001), and tamoxifen t max was shorter (2.1 vs. 8.1 h; P = 0.001), indicating variation in absorption. Systemic exposure (AUC0-24 h) to endoxifen was 15 % higher (P < 0.001) following morning administration. The results suggest that dosing time is of marginal influence on tamoxifen pharmacokinetics. Our study was not designed to detect potential changes in clinical outcome or toxicity, based on a difference in the time of administration. Circadian rhythm may be one of the many determinants of the interpatient and intrapatient pharmacokinetic variability of tamoxifen.
    Breast Cancer Research and Treatment 06/2015; 152(1). DOI:10.1007/s10549-015-3452-x · 3.94 Impact Factor
  • Teun van Gelder ·
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    ABSTRACT: Generic immunosuppressive drugs are available in Europe, Canada, and the United States. Between countries, there are large differences in the market penetration of generic drugs in general, and for immunosuppressive drugs in particular. The registration criteria for generic immunosuppressive drugs are often criticized. However, it is unlikely that the criteria for registration of narrow therapeutic index drugs are going to change, and bioequivalence studies, performed in healthy volunteers, will remain the backbone of the registration process. It would be good if the registration authorities would demand that all generic variants of an innovator drug have the same pill appearance to reduce errors and promote drug adherence.To allow for safe substitution, a number of criteria need to be fulfilled. Generic substitution should not be taken out of the hands of the treating physicians. Generic substitution can only be done safely if initiated by the prescriber, and in well-informed and prepared patients. Payers should refrain from forcing pharmacists to dispense generic drugs in patients on maintenance treatment with innovator drug. Instead, together with transplant societies, they should design guidelines on how to implement generic immunosuppressive drugs into clinical practice. Substitutions must be followed by control visits to check if the patient is taking the medication correctly and if drug exposure remains stable. Inadvertent, uncontrolled substitutions from 1 generic to another, initiated outside the scope of the prescriber, must be avoided as they are unsafe. Repetitive subsequent generic substitutions result in minimal additional cost savings and have an inherent risk of medication errors.
    Transplantation 06/2015; DOI:10.1097/TP.0000000000000782 · 3.83 Impact Factor
  • Yun-Ying Shi · Dennis A. Hesselink · Teun van Gelder ·
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    ABSTRACT: Elderly patients are a fast growing population among transplant recipients over the past decades. Both the innate and adaptive immune reactivity decrease with age, which is believed to contribute to the decreased incidence of acute rejection and increased infectious death rate in elderly transplant recipients. In contrast to recipient age, donor age is associated with a higher incidence of acute rejection. Pharmacokinetic studies in renal transplant recipients show that CNI troughs are >5% higher in elderly compared to younger patients given the same dose normalized by body weight. This may impact the starting dose of tacrolimus and cyclosporine. Possibly in elderly patients the intracellular (in lymphocyte) concentrations are relatively high in relation to the whole blood concentration, resulting in a stronger pharmacodynamic effect at the same whole blood trough concentration. For cyclosporine this has been shown, but it is not clear if the same is true for other immunosuppressive drugs. Pharmacodynamic studies have compared the inhibition of target enzymes, or more downstream effects of immunosuppressive drugs, in younger and older patients. Measurement of nuclear factor of activated T-cell (NFAT)-regulated gene expression (RGE), a pharmacodynamic read-out of CNI, is a promising biomarker of immunosuppression. Low levels of NFAT RGE are associated with increased risk of infection and non-melanoma skin cancer in elderly patients. Clinical trials to evaluate the safety and efficacy of immunosuppression regimens in this specific patient population, which is underrepresented in published trials, are lacking. More studies in elderly patients are needed to investigate the impact of age on the pharmacokinetics or pharmacodynamics of immunosuppressive drugs, and to decide on the optimal regimen and target levels for elderly transplant recipients. Copyright © 2015. Published by Elsevier Inc.
    Transplantation Reviews 05/2015; DOI:10.1016/j.trre.2015.04.007 · 3.82 Impact Factor
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    ABSTRACT: Introduction: Starting doses of tacrolimus and ciclosporin are typically chosen on a calculated mg/kg bodyweight basis. After initiation of treatment, doses are adjusted with therapeutic drug monitoring (TDM). This trial-and-error approach has been accepted by most physicians and pharmacists involved in the care of transplanted patients. Areas covered: Dosing algorithms have only fairly recently been proposed to better individualize the starting dose. This review provides an overview of all the currently available dosing algorithms in adult and children for the starting dose of ciclosporin, tacrolimus and mycophenolic acid. In these algorithms, multiple other covariates influencing the starting dose, such as age, hematocrit, comedication and genotype are taken into account. After selecting the starting dose with an algorithm and after initiation of treatment, TDM will, however, remain necessary. Whether or not implementation of such algorithms will improve clinical outcome remains to be demonstrated. Expert opinion: First of all an algorithm needs to be validated, against an independent dataset. Second, in a prospective study the algorithm should prove to reduce the time to reach the target concentration, and to reduce the number of patients with drug concentrations (far) outside the therapeutic window. Finally, a clinical trial demonstrating a benefit on clinical outcome will be crucial in achieving broad acceptance of calculating starting dose using individualized dosing algorithms.
    Expert Opinion on Drug Metabolism &amp Toxicology 04/2015; 11(6):1-16. DOI:10.1517/17425255.2015.1033397 · 2.83 Impact Factor
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    Annals of Oncology 04/2015; 26(6). DOI:10.1093/annonc/mdv169 · 7.04 Impact Factor
  • Teun van Gelder · Dennis A Hesselink ·
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    ABSTRACT: The patent of mycophenolate mofetil (MMF) has expired and for enteric coated-mycophenolate sodium (EC-MPS) this will happen in 2017. In the twenty years these drugs have been used, they have become extremely popular. In this review the reasons for the popularity of mycophenolate are discussed, including the benefits compared to azathioprine. MMF and EC-MPS are therapeutically equivalent. Although neither is considered to be a narrow therapeutic index drug, this should not lead to careless switching between the innovator drug and generic formulations, or between one generic formulation to another. The pipeline of new immunosuppressive drugs is dry, and it is very likely that we will be using mycophenolate for many more years to come as a first line immunosuppressive drug in our transplant population. Whether or not the development of donor-specific anti-HLA antibodies is related to drug exposure (mycophenolic acid concentrations) remains to be investigated. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Transplant International 03/2015; 28(5). DOI:10.1111/tri.12554 · 2.60 Impact Factor
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    ABSTRACT: AimEducating physicians in the procedural as well as cognitive skills of IT-mediated medication management could be one of the missing links for improvement of patient safety. We aimed to compose a framework of tasks that need to be addressed to optimize medication management in outpatient care.Methods Formal task analysis: decomposition of a complex task into a set of subtasks. First, we obtained a general description of the medication management process from exploratory interviews. Secondly, we interviewed experts in-depth to further define tasks and subtasks. Setting: Outpatient care in different fields of medicine in six teaching and academic medical centers in the Netherlands and the United States. Participants: 20 experts. Tasks were decomposed into procedural, cognitive and macrocognitive tasks and categorized into the three components of dynamic decision-making.ResultsThe medication management process consists of three components: (1) reviewing the medication situation, (2) composing a treatment plan, and (3) accomplishing and communicate a treatment and surveillance plan. Subtasks include multiple cognitive tasks such as composing a list of current medication and evaluating the reliability of sources, and procedural tasks such as documenting current medication. The identified macrocognitive tasks were: planning, integration of information technology (IT) in workflow, managing uncertainties and responsibilities, and problem detection.Conclusion All identified procedural, cognitive and macrocognitive skills should be included when designing education for IT-mediated medication management. The resulting framework supports the design of educational interventions to improve IT-mediated medication management in outpatient care.
    British Journal of Clinical Pharmacology 03/2015; 80(3). DOI:10.1111/bcp.12625 · 3.88 Impact Factor
  • Eric C T Geijteman · Teun van Gelder · Lia van Zuylen ·

    JAMA Internal Medicine 01/2015; 175(3). DOI:10.1001/jamainternmed.2014.7592 · 13.12 Impact Factor
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    ABSTRACT: Drug-drug interactions (DDIs) are of major concern in oncology, since cancer patients typically take many concomitant medications. Retrospective studies have been conducted to determine the prevalence of DDIs. However, prospective studies on DDIs needing interventions in cancer patients have not yet been performed. Therefore, a prospective study was designed to identify DDIs leading to interventions among ambulatory cancer patients receiving anticancer treatment. Patients starting with a new treatment regimen with intravenous or oral anticancer medication were asked to participate. The patients' medication was checked for DDIs by using drug interaction software. An expert team of clinical pharmacologists evaluated the relevance of these identified DDIs. If a DDI was qualified as potentially clinically relevant, an intervention was proposed to the treating (hemato)oncologist. Several variables were studied as determinants for performing an intervention. Descriptive statistics and uni- and multivariate logistic regression analyses were performed. In this study 302 patients were included. A total of 603 DDIs were identified by the drug interaction software and judged by the expert team. Of all 603 DDIs, 120 DDIs were considered potentially clinically relevant. These 120 DDIs, present in a total of 81 patients, resulted in a clinical intervention already executed by the (hemato)oncologist in 39 patients (13%), while an additional intervention was proposed by a clinical pharmacologist in 42 patients (14%). The number of comorbidities and the number of "over-the-counter"-drugs were identified as determinants. Clinical interventions on DDIs are frequently required among patients starting with anticancer therapy. Structured screening for these potentially clinically relevant DDIs, by (hemato)oncologists in close collaborations with clinical pharmacologists, should take place before the start and during anticancer treatment. This study was registered at the Dutch Trial Registry under number NTR3760. © 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 01/2015; 26(5). DOI:10.1093/annonc/mdv029 · 7.04 Impact Factor

Publication Stats

8k Citations
1,406.68 Total Impact Points


  • 2002-2015
    • Erasmus MC
      • Department of Internal Medicine
      Rotterdam, South Holland, Netherlands
    • University Medical Center Utrecht
      Utrecht, Utrecht, Netherlands
  • 1989-2015
    • Erasmus Universiteit Rotterdam
      • • Department of Internal Medicine
      • • Institute of Health Policy & Management (iBMG)
      Rotterdam, South Holland, Netherlands
  • 2007
    • Georg-August-Universität Göttingen
      Göttingen, Lower Saxony, Germany
  • 2000-2004
    • Stanford Medicine
      • Department of Cardiothoracic Surgery
      Stanford, California, United States
  • 1999-2002
    • Stanford University
      • Department of Cardiothoracic Surgery
      Stanford, California, United States
  • 2001
    • University of California, San Francisco
      • School of Pharmacy
      San Francisco, California, United States
  • 1999-2001
    • Leiden University
      Leyden, South Holland, Netherlands