Teun van Gelder

Erasmus MC, Rotterdam, South Holland, Netherlands

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Publications (310)1290.89 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: 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; DOI:10.1517/17425255.2015.1033397 · 2.93 Impact Factor
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    Annals of Oncology 04/2015; DOI:10.1093/annonc/mdv169 · 6.58 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 · 3.16 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; DOI:10.1111/bcp.12625 · 3.69 Impact Factor
  • JAMA Internal Medicine 01/2015; DOI:10.1001/jamainternmed.2014.7592 · 13.25 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.
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    ABSTRACT: Nonadherence to immunosuppressive medication after kidney transplantation is a behavioral issue and as such it is important to understand the psychological factors that influence this behavior. The aim of this study was to investigate the extent to which goal cognitions, illness perceptions, and treatment beliefs were related to changes in self-reported immunosuppressive medication adherence up to 18 months after transplantation. Interviews were conducted with patients in the outpatient clinic 6 weeks (T1; n = 113), 6 months (T2; n = 106), and 18 months (T3; n = 84) after transplantation. Self-reported adherence was measured using the Basel Assessment of Adherence to Immunosuppressive Medications Scale Interview. Psychological concepts were measured using the Brief Illness Perceptions Questionnaire, Beliefs about Medicines Questionnaire, and questions on the importance of adherence as a personal goal, conflict with other goals, and self-efficacy for goal attainment. Nonadherence significantly increased over time to 31% at T3. Perceived necessity of medication, perceived impact of transplant on life (consequences) and emotional response to transplantation significantly decreased over time. Participants who reported low importance of medication adherence as a personal goal were more likely to become nonadherent over time. Illness perceptions can be described as functional and supportive of adherence which is inconsistent with the pervasive and increasing nonadherence observed. There appears therefore to be a discrepancy between beliefs about adherence and actual behavior. Promoting (intrinsic) motivation for adherence goals and exploring the relative importance in comparison to other personal goals is a potential target for interventions.
    Transplantation 01/2015; DOI:10.1097/TP.0000000000000608 · 3.78 Impact Factor
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    ABSTRACT: Clinical response to tamoxifen varies widely among women treated with this drug for hormone receptor-positive breast cancer. The principal active metabolite – endoxifen – is generated through hepatic metabolism of tamoxifen, with key roles for cytochrome P450 (CYP) CYP2D6 and CYP3A. By influencing endoxifen formation, genetic variants of CYP2D6 may affect response to tamoxifen. After a decade of research, examining the effects of CYP2D6 genetic variants on tamoxifen efficacy, there is still no agreement on the clinical utility of CYP2D6 genotype as biomarker for the prediction of breast cancer outcome, because studies revealed conflicting results. However, tamoxifen metabolism is complex and involves several other drug-metabolizing enzymes. Genetic variants of other CYP enzymes, including CYP3A4 and CYP2C9/19, as well as co-medication interfering with the metabolic activity of CYP2D6 and CYP3A4 have been shown to affect endoxifen concentrations and may also contribute to the variability in response to tamoxifen. Phenotyping strategies can predict endoxifen exposure more accurately than CYP2D6 genotype, but do not take into account all factors influencing endoxifen exposure. Therapeutic drug monitoring (TDM) is likely to be the optimal strategy for individualization of tamoxifen treatment. According to a growing amount of literature, endoxifen concentration seems to be a predictor of clinical outcome. The relationship between endoxifen levels and breast cancer outcomes has to be replicated and confirmed and the value of TDM should be evaluated in prospective clinical trials. Caution is advised regarding the concomitant use of medications which could interact with tamoxifen, including inhibitors and inducers of CYP enzymes.
    Cancer Treatment Reviews 01/2015; 41(3). DOI:10.1016/j.ctrv.2015.01.002 · 6.47 Impact Factor
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    ABSTRACT: Tacrolimus (Tac) is widely used for the prevention of rejection after solid organ transplantation. Finding the optimal balance between effective Tac concentrations and toxicity is a challenge and requires therapeutic drug monitoring. In addition to the well-known inter-patient variability, the clinical use of Tac is also complicated by considerable intra-patient variability (IPV) in Tac exposure. Tac IPV is defined as the amount of fluctuation of whole-blood concentrations over a certain period of time during which the Tac dose remains unchanged. A high IPV in Tac exposure has recently been recognized as a strong risk factor for acute rejection and poor long-term kidney transplantation outcome. In addition to non-adherence, several other factors determine the magnitude of the IPV in Tac exposure. Quantification of IPV is easy and can be easily incorporated into everyday clinical practice as a tool for optimizing transplantation outcomes. Copyright © 2015 Elsevier Inc. All rights reserved.
    Transplantation Reviews 01/2015; DOI:10.1016/j.trre.2015.01.002 · 2.68 Impact Factor
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    ABSTRACT: Biologic drugs ('biologics'), have revolutionized the treatment of patients with extensive and therapy-resistant psoriasis. Unfortunately, biologics (the anti-TNFα agents adalimumab, infliximab and etanercept, and the anti-p40(IL12/23) ustekinumab) appear to lose efficacy over time and many patients are eventually switched to another biologic This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    British Journal of Dermatology 12/2014; DOI:10.1111/bjd.13573 · 4.10 Impact Factor
  • The Lancet Oncology 10/2014; 15(11):e470–e471. DOI:10.1016/S1470-2045(14)70459-0 · 24.73 Impact Factor
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    Conference Paper: ESMO 2014, Madrid
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    ABSTRACT: Drug-drug interactions in patients treated for cancer: a prospective study on clinical interventions
    ESMO 2014, Madrid; 09/2014
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    ABSTRACT: Background: Intra-patient variability (IPV) in tacrolimus exposure is associated with renal allograft failure. The aim of this study was to investigate whether conversion from the twice-daily tacrolimus formulation (Tac-TD) to a once-daily formulation (Tac-OD) leads to a lower IPV in tacrolimus exposure. Methods: Two hundred and forty seven stable renal transplant recipients were converted from Tac-TD to Tac-OD (Advagraf(R)) on a 1 mg:1 mg total daily dose basis. After conversion, patients were followed for 12 months and tacrolimus predose whole-blood concentrations (C0), serum creatinine, eGFR, and proteinuria were measured. These parameters were compared with those collected at all outpatient visits in the 12-month period (+/-3 months) before conversion (Tac-TD period). The IPV was calculated based on the dose-adjusted tacrolimus C0. Results: The Tac-OD formulation provided an excellent graft survival (100%), a low acute rejection rate (0.8%), and good tolerability. Renal function remained stable: eGFR 48 (16-90) mL/min vs. 46 (12-90) mL/min (p=0.15) before and after conversion, respectively. After conversion to Tac-OD, mean C0 was significantly lower, decreasing from 5.7 +/- 1.5 ng/mL to 5.0 +/-1.5 ng/mL, corresponding to a 12% reduction (p < 0.01). Both drugs had similar IPVs (Tac-TD: 17.3 +/-1.6% vs. Tac-OD: 16.4 +/-1.6%; p =0.31). Conclusions: Although conversion from Tac-TD to Tac-OD significantly reduces tacrolimus exposure as measured by C0, and appears safe, it does not reduce IPV in tacrolimus exposure.
    Therapeutic Drug Monitoring 09/2014; 37(2). DOI:10.1097/FTD.0000000000000136 · 1.93 Impact Factor
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    ABSTRACT: The transplantation literature includes numerous papers that report associations between polymorphisms in genes encoding metabolizing enzymes and drug transporters, and pharmacokinetic data on immunosuppressive drugs. Most of these studies are retrospective in design, and although a substantial number report significant associations, pharmacogenetic tests are hardly used in clinical practice. One of the reasons for this poor implementation is the current lack of evidence of improved clinical outcome with pharmacogenetic testing. Furthermore, with efficient therapeutic drug monitoring it is possible to rapidly correct for the effect of genotypic deviations on pharmacokinetics, thereby decreasing the utility of genotype-based dosing. The future of pharmacogenetics will be in treatment models in which patient characteristics are combined with data on polymorphisms in multiple genes. These models should focus on pharmacodynamic parameters, variations in the expression of drug transporter proteins, and predictors of toxicity. Such models will provide more information than the relatively small candidate gene studies performed so far. For implementation of these models into clinical practice, linkage of genotype data to medication prescription systems within electronic health records will be crucial.
    Nature Reviews Nephrology 09/2014; DOI:10.1038/nrneph.2014.172 · 8.37 Impact Factor
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    ABSTRACT: This overview describes the full spectrum of current pre-clinical and clinical kidney-, liver-, heart- and lung transplantation research performed in Erasmus MC – University Medical Centre in Rotterdam, The Netherlands. An update is provided on the development of a large living donor kidney transplantation program and on optimization of kidney allocation, including the implementation of a domino kidney-donation program. Our current research efforts to optimize immunosuppressive regiments and find novel targets for immunosuppressive therapy, our recent studies on prevention of ischemia-reperfusion-induced graft injury, our newest findings on stimulation of tissue regeneration, our novel approaches to prevent rejection and viral infection, and our latest insights in the regulation of allograft rejection, are summarized.
    Transplant Immunology 09/2014; DOI:10.1016/j.trim.2014.09.005 · 1.83 Impact Factor
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    ABSTRACT: Chronic kidney disease (CKD) after liver transplantation (LT) is a major clinical problem that appears to be associated with nongenetic as well as genetic determinants. Calcineurin inhibitor (CNI) use is considered to play a major role in the development of CKD after LT. We studied the influence of single-nucleotide polymorphisms (SNPs) in the genes of the donor and recipient CNI-metabolizing enzyme CYP3A5 and the CNI-transporting ABCB1 on the development of CKD after LT.
    Pharmacogenetics and Genomics 07/2014; DOI:10.1097/FPC.0000000000000063 · 3.45 Impact Factor
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    ABSTRACT: Several lines of evidence suggest a T cell-mediated immune response in paraneoplastic neurological syndromes with anti-Hu antibodies (Hu-PNS). In order to investigate whether suppression of T cell-mediated immune responses in Hu-PNS patients improved their neurological outcome, we performed a prospective open-label, single-arm study on sirolimus.
    Neuro-Oncology 07/2014; DOI:10.1093/neuonc/nou126 · 5.29 Impact Factor
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    ABSTRACT: In the past decade, many tyrosine-kinase inhibitors have been introduced in oncology and haemato-oncology. Because this new class of drugs is extensively used, serious drug-drug interactions are an increasing risk. In this Review, we give a comprehensive overview of known or suspected drug-drug interactions between tyrosine-kinase inhibitors and other drugs. We discuss all haemato-oncological and oncological tyrosine-kinase inhibitors that had been approved by Aug 1, 2013, by the US Food and Drug Administration or the European Medicines Agency. Various clinically relevant drug interactions with tyrosine-kinase inhibitors have been identified. Most interactions concern altered bioavailability due to altered stomach pH, metabolism by cytochrome P450 isoenzymes, and prolongation of the QTc interval. To guarantee the safe use of tyrosine-kinase inhibitors, a drugs review for each patient is needed. This Review provides specific recommendations to guide haemato-oncologists, oncologists, and clinical pharmacists, through the process of managing drug-drug interactions during treatment with tyrosine-kinase inhibitors in daily clinical practice.
    The Lancet Oncology 07/2014; 15(8):e315-e326. DOI:10.1016/S1470-2045(13)70579-5 · 24.73 Impact Factor
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    ABSTRACT: Hypertension is a common side effect of calcineurin inhibitors (CNIs), which are drugs used to prevent rejection after transplantation. Hypertension after kidney transplantation has been associated with earlier graft failure and higher cardiovascular mortality in the recipient. Recent data indicate that enzymes and transporters involved in CNI pharmacokinetics and pharmacodynamics, including CYP3A5, ABCB1, WNK4 and SPAK, are also associated with salt-sensitive hypertension. These insights raise the question whether polymorphisms in the genes encoding these proteins increase the risk of CNI-induced hypertension. Predicting who is at risk for CNI-induced hypertension may be useful for when selecting specific interventions, including dietary salt restriction, thiazide diuretics or a CNI-free immunosuppressive regimen. This review aims to explore the pharmacogenetics of CNI-induced hypertension, highlighting the knowns and unknowns.
    Pharmacogenomics 06/2014; 15(9):1243-51. DOI:10.2217/pgs.14.87 · 3.43 Impact Factor
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    ABSTRACT: Mycophenolate mofetil (MMF) is used to prevent acute rejection following solid organ transplantation in transplant centers all over the world. Patients from different ethnic backgrounds are treated with this drug, for which therapeutic drug monitoring (TDM) has not become the standard of practice in most centers. Whether or not some ethnic groups require a different MMF dose has been a topic of debate in recent years.In this review it is shown that Asian patients, compared to Caucasian patients, with a comparable MMF dose reach higher mycophenolic acid (MPA) exposure. Also clinical experience points towards more adverse events in case of treatment with 1 gram MMF bid in Asian patients, and therefore for this ethnic group a lower maintenance dose seems justified. In contrast, African American patients reach similar drug concentrations as Caucasians patients receiving the same MMF dose but due to immunological reasons they require a higher MMF dose to reach comparable acute rejection incidences.When TDM is performed clinicians can correct the dose and compensate for inter-ethnic differences in drug exposure. Otherwise, it is important to choose the right dose. This optimal dose is 20%-46% lower in Asian transplant recipients than in Caucasian or African American patients.This article is protected by copyright. All rights reserved.
    Transplant International 06/2014; 27(10). DOI:10.1111/tri.12382 · 3.16 Impact Factor

Publication Stats

6k Citations
1,290.89 Total Impact Points

Institutions

  • 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
      • • Department of Clinical Chemistry
      • • Institute of Health Policy & Management (iBMG)
      • • Department of Surgery
      Rotterdam, South Holland, Netherlands
  • 2013
    • Catholic University of Louvain
      • Louvain Centre for Toxicology and Applied Pharmacology
      Лувен-ла-Нев, Walloon, Belgium
    • University of Adelaide
      • Discipline of Clinical and Experimental Pharmacology
      Tarndarnya, South Australia, Australia
  • 2011
    • The Queen Elizabeth Hospital
      • Department of Clinical Pharmacology
      Tarndarnya, South Australia, Australia
  • 2006
    • Tufts University
      Бостон, Georgia, United States
  • 2001–2004
    • Stanford Medicine
      • Department of Cardiothoracic Surgery
      Stanford, California, United States
  • 1999–2001
    • Leiden University
      Leyden, South Holland, Netherlands
    • Stanford University
      • Department of Cardiothoracic Surgery
      Palo Alto, California, United States