Judith A M Wessels

Leiden University Medical Centre, Leiden, South Holland, Netherlands

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Publications (41)234.7 Total impact

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    ABSTRACT: Busulfan is used in preparative regimens before stem cell transplantation. There is significant interpatient variability in busulfan pharmacokinetics (PK) and exposure is related to outcome. Polymorphisms in genes encoding glutathione-S-transferases have been associated with busulfan PK but only explain a limited portion of the observed variability. The aim of this study is to identify additional genetic variants associated with busulfan PK by interrogating 1936 variants in 225 genes involved in drug absorption, distribution, metabolism, and excretion (ADME). In an exploratory cohort (n=65), patients who received busulfan were genotyped with the DMET array. Top SNPs and haplotypes associated with busulfan clearance were validated in an independent validation cohort (n=78). In the exploratory cohort, seven variants were identified to be associated with busulfan clearance (P<0.001). In the validation cohort, only GSTA5 (rs4715354 and rs7746993) remained significantly associated with busulfan clearance (P=0.025). This is the first study using an exploratory pharmacogenetic approach to explain the interindividual variability in busulfan PK. The role of glutathione-S-transferases was confirmed, but no additional genetic markers involved in drug ADME appear to be associated with busulfan PK.
    Pharmacogenetics and Genomics 12/2013; 23(12):675-83. · 3.45 Impact Factor
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    ABSTRACT: In tamoxifen-treated breast cancer patients the occurrence of hot flashes may be associated with effective estrogen receptor antagonism dependent on genetic variations of metabolic enzymes and the estrogen receptor. Early breast cancer patients who were randomized to receive tamoxifen, followed by exemestane within the tamoxifen exemestane adjuvant multinational trial were genotyped for five CYP2D6 alleles. CYP2D6 genotypes and phenotypes were related to the occurrence of hot flashes as adverse event during the first year of tamoxifen use (primary aim) and the time to the occurrence of hot flashes as AE during the complete time on tamoxifen (secondary aim). In addition, exploratory analyses on 22 genetic variants of other metabolic enzymes and two common polymorphisms in the estrogen receptor-1 were performed. No association was found between the CYP2D6 genotype/phenotype or any other genetic variant and hot flashes during the first year. Only higher age was related to a lower incidence of hot flashes in the first year (adjusted odds ratio 0.94, 95 % CI 0.92-0.96; p < 0.001). The ESR1 PvuII XbaI CG haplotype was associated with the time to the occurrence of hot flashes during the complete time on tamoxifen (CG/CG vs. CG/other + other/other: adjusted hazard ratio 0.49, 95 % CI 0.25-0.97; p = 0.04). In conclusion, the CYP2D6 genotypes and phenotypes were not associated with the occurrence of hot flashes. Common polymorphisms in the estrogen receptor-1 might predict hot flashes as common tamoxifen side effect, although this finding needs replication.
    Breast Cancer Research and Treatment 11/2013; · 4.47 Impact Factor
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    ABSTRACT: The clinical importance of CYP2D6 genotype as predictor of tamoxifen efficacy is still unclear. Recent genotyping studies on CYP2D6 using DNA derived from tumor blocks have been criticized because loss of heterozygosity (LOH) in tumors may lead to false genotype assignment. Postmenopausal early breast cancer patients who were randomized to receive tamoxifen, followed by exemestane in a large randomized controlled trial were genotyped for five CYP2D6 alleles. CYP2D6 genotypes and phenotypes were related to disease-free survival during tamoxifen use (DFS-t) in 731 patients. By analyzing microsatellites flanking the CYP2D6 gene, patients whose genotyping results were potentially affected by LOH were excluded. In addition, exploratory analyses on 24 genetic variants of other metabolic enzymes and the estrogen receptor were performed. For the CYP2D6 analysis, only 2.3 % of the samples were excluded, because influence of LOH could not be ruled out. No association was found between the CYP2D6 genotype or predicted phenotype and DFS-t (poor vs. extensive metabolizers: unadjusted hazard ratio 1.33, 95 % CI 0.52-3.43; P = 0.55). DFS-t was associated with UGT2B15*2 (Vt/Vt + Wt/Vt vs. Wt/Wt: adjusted hazard ratio 0.47, 95 % CI 0.25-0.89; P = 0.019) and the estrogen receptor-1 polymorphism ESR1 PvuII (gene-dose effect: adjusted hazard ratio 1.63, 95 % CI 1.04-2.54; P = 0.033). In postmenopausal early breast cancer patients treated with adjuvant tamoxifen followed by exemestane neither CYP2D6 genotype nor phenotype did affect DFS-t. This is in accordance with two recent studies in the BIG1-98 and ATAC trials. Our study is the first CYP2D6 association study using DNA from paraffin-embedded tumor tissue in which potentially false interpretation of genotyping results because of LOH was excluded. Polymorphisms in the estrogen receptor-1 and UGT2B15 may be associated with tamoxifen efficacy, but these findings need replication.
    Breast Cancer Research and Treatment 07/2013; · 4.47 Impact Factor
  • European Heart Journal 04/2013; · 14.72 Impact Factor
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    ABSTRACT: Abstract Background: Statins and coumarins are prescribed in combination on a regular basis. Some case reports suggested that statins might affect the dose requirements of coumarins. The aim of the study was to investigate whether acenocoumarol and phenprocoumon maintenance doses are influenced by statin use. Methods: The Pre-EU-PACT database was used, which contains information on 471 acenocoumarol and 624 phenprocoumon users. The influence of individual statins on the acenocoumarol and phenprocoumon maintenance dose was investigated by comparing unadjusted and adjusted mean differences of the maintenance dose between statin and non-statin users. Results: Lower adjusted acenocoumarol dose requirements were observed for patients using atorvastatin, simvastatin, pravastatin, and rosuvastatin. These patients had a reduction in adjusted mean acenocoumarol maintenance dose of 0.11, 0.29, 0.38, and 0.69 mg/day, respectively, compared with a mean adjusted dose of 2.60 mg/day for the patients not using a statin. There was no significant effect of statin use on unadjusted and adjusted phenprocoumon maintenance dose (p=0.23 and p=0.35, respectively). Conclusions: Mean acenocoumarol maintenance dosages were decreased when acenocoumarol is co-administered with the different statins. Statin use does not affect phenprocoumon maintenance doses significantly.
    Drug metabolism and drug interactions 09/2012;
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    ABSTRACT: Hypertension is an important side effect of sunitinib treatment. In a retrospective study in 255 patients, single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor (VEGFR)-2, endothelin-1 (ET-1), and endothelium-derived nitric oxide synthase (eNOS) were multivariately tested against hypertension grades and changes in systolic blood pressure (SBP), diastolic BP (DBP), and mean arterial BP (MAP). Next, the association between hypertension and survival in patients with metastatic renal cell cancer (mRCC) was studied. Greater elevations in SBP and MAP were associated with the presence of a haplotype in VEGFA (P = 0.014 and P = 0.036, respectively). The tendency to develop grade 3 hypertension was associated with this haplotype and also with a SNP in eNOS (P = 0.031 and P = 0.045, respectively). In mRCC patients, sunitinib-induced hypertension was found to confer a survival benefit, with the mean overall survival being prolonged by 7.2 months (P = 0.035 and P = 0.026 for SBP and DBP elevations, respectively). Genetic polymorphisms in VEGFA and eNOS independently predict rise in BP and/or development of severe hypertension in sunitinib-treated patients. Grade 3 hypertension was found to be an independent factor for overall survival in patients with mRCC.
    Clinical Pharmacology &#38 Therapeutics 09/2012; 92(4):503-10. · 6.85 Impact Factor
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    ABSTRACT: BACKGROUND: Antiplatelet drug resistance is a well-known problem, causing recurrent cardiovascular events. Multiple genetic polymorphisms have been related to antiplatelet resistance by several large trials, however data from common clinical practice is limited. We examined the influence of previously described polymorphisms, related to aspirin and clopidogrel resistance, on treatment outcome in a real life unselected population of patients presenting with ST-segment elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention. METHODS AND RESULTS: This cohort study consisted of 1327 patients with STEMI. Patients were treated according to a standardized guideline-based protocol. Nine polymorphisms, COX1 (-842A>G), P2Y(1) (893C>T), GPIa (807C>T), GPIIIa (PlA1/A2), CYP2C19 (*2, *3 and *17), ABCB1 (3435T>C) and PON1 (576A>G), were genotyped. During 1year of follow up the primary endpoint, a composite of cardiac death or recurrent myocardial infarction, was reached in 86 patients. The COX1 and CYP2C19*2 polymorphisms were associated with the primary endpoint, HR 2.55 (95% CI 1.48-4.40), P=0.001 and HR 2.03 (1.34-3.09) P=0.001, respectively. The combined analysis demonstrated a 2.5-fold increased risk for individuals with ≥2 risk alleles, P=6.9×10(-9). The association of COX1 was driven by mortality related events whereas that of CYP2C19*2 was mainly attributed to myocardial infarction and stent thrombosis. CONCLUSION: In this unselected, real life population of STEMI patient on dual-antiplatelet therapy, the polymorphisms COX1 -842A>G and CYP2C19*2 were determinants of thrombotic complications during follow-up. We show that in a clinical setting, testing for these polymorphisms could be of value in the identification of STEMI patients at risk for recurrent cardiovascular events.
    International journal of cardiology 08/2012; · 6.18 Impact Factor
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    ABSTRACT: To evaluate the performance of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) acenocoumarol dose algorithms in an independent data set. The EU-PACT trial investigates the added value of pretreatment genotyping for use of warfarin, phenprocoumon and acenocoumarol. External validation was performed in the Rotterdam Study cohort using information about 707 acenocoumarol users. R(2), which measures the strength of correlation between the predicted and observed acenocoumarol dose, mean absolute error and mean squared error were calculated to evaluate the performance of the original algorithm. Validation resulted in a R(2) of 52.7 and 12.9% compared with an R(2) of 52.6 and 17.8% in the original study for the genotype-guided and nongenotype-guided dose algorithm, respectively. For the genotype-guided dose algorithm, the mean absolute error was 0.48 mg/day and the mean squared error was 0.38 (mg/day)(2). For the nongenotype-guided dose algorithm, the mean absolute error was 0.62 mg/day and the mean squared error was 0.63 (mg/day)(2). The EU-PACT acenocoumarol algorithm performs just as accurately in this study as in the original study, which implies applicability in various populations.
    Pharmacogenomics 08/2012; 13(11):1239-45. · 3.43 Impact Factor
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    ABSTRACT: The performance of a clinical pharmacogenetic model to predict nonresponse of methotrexate (MTX) monotherapy in patients with established rheumatoid arthritis (RA) and failure of disease-modifying antirheumatic drugs (DMARDs) was studied. For 75 RA patients receiving MTX monotherapy for 6 months, DNA and clinical data were available. Risk scores for nonresponse at 6 months (disease activity score >2.4), were calculated using the pharmacogenetic prediction model utilizing four clinical factors and four polymorphisms in the genes MTHFD1, AMPD1, ITPA and ATIC. At 6 months, there were 25 responders and 50 nonresponders. Using the clinical pharmacogenetic prediction model, 75% (56 out of 75) were categorized into predicted responders (risk score ≤ 3.5) and predicted nonresponders (risk score ≥ 6). At 6 months, the negative predictive value was 81% (21 out of 26) and the positive predictive value was 47% (14 out of 30). The pharmacogenetic model predicts nonresponse to MTX monotherapy, but performs better in DMARD naive recent-onset RA patients than in patients with preceding DMARD failure.
    Pharmacogenomics 07/2012; 13(9):1087-94. · 3.43 Impact Factor
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    ABSTRACT: Previous studies have provided contradictory results regarding the interaction between the CYP2C9 and VKORC1 genotypes affecting various outcome measures. We aimed to provide a definite answer regarding the question whether there exists a gene-gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol. The EU-PACT cohort dataset, which contains data on 624 phenprocoumon and 471 acenocoumarol patients, was used. Patient characteristics, pharmacogenetic data, International Normalized Ratios (INRs) and dosages were available. We investigated whether there was an interaction between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability during the first 180 days of phenprocoumon and acenocoumarol therapy, in addition to the effect of the separate genotypes. The interaction effect was investigated by adding the product term of the CYP2C9 and VKORC1 genotype classes for four different commonly used CYP2C9 classifications to the linear regression model - for the outcome measure maintenance dose - or to the Cox regression models - for the outcome measures time to severe over-anticoagulation and time to achieve stability. No significant interactions - all P-values above 0.23 for phenprocoumon and 0.30 for acenocoumarol - were observed for all outcome measures. There are no interactions between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability for phenprocoumon and acenocoumarol.
    Journal of Thrombosis and Haemostasis 03/2012; 10(5):767-72. · 6.08 Impact Factor
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    ABSTRACT: The required acenocoumarol dose and the risk of underanticoagulation and overanticoagulation are associated with the CYP2C9 and VKORC1 genotypes. However, the duration of the effects of these genes on anticoagulation is not yet known. In the present study, the effects of these polymorphisms on the risk of underanticoagulation and overanticoagulation over time after the start of acenocoumarol were investigated. In three cohorts, we analyzed the relationship between the CYP2C9 and VKORC1 genotypes and the incidence of subtherapeutic or supratherapeutic International Normalized Ratio (INR) values (< 2 and > 3.5) or severe overanticoagulation (INR > 6) for different time periods after treatment initiation. Patients with polymorphisms in CYP2C9 and VKORC1 had a higher risk of overanticoagulation (up to 74%) and a lower risk of underanticoagulation (down to 45%) in the first month of treatment with acenocoumarol, but this effect diminished after 1-6 months. Knowledge of the patient's genotype therefore might assist physicians to adjust doses in the first month(s) of therapy.
    Journal of Thrombosis and Haemostasis 01/2012; 10(4):606-14. · 6.08 Impact Factor
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    ABSTRACT: The 5-hydroxytryptamine (5-HT3) receptor is a ligand-operated ion channel with five different receptor subunits (5-HT3A, B, C, D, and E) found in humans. Activation of 5-HT3 receptors influences various effects such as drug-induced emesis and causes behavioral problems such as anxiety, depression and cognitive disorders. To explore interethnic differences in the response to 5-HT3 antagonists, we studied haplotype frequencies in the gene encoding the 5-HT3B receptor in Asians and Caucasians. Three single nucleotide polymorphisms (SNPs) of the 5-HT3B receptor gene, i.e., deletion AAG at the 5'-UTR position, 18792A>G at the intron position, and 46698G>A at the 3' near gene position, were selected and genotyped in 165 Indonesian cancer patients and 188 Caucasian healthy volunteers. Haplotypes were set with gPlink, whereas the differences in haplotype frequencies between Indonesians and Caucasians were compared using multivariate analysis. The haplotype profiles based on the deletion AAG, 18792A>G and 46698G>A were AAGAA, AAGAG, AAGGG, and deletion AG in both Indonesians and Caucasians. The frequency of the AAGAG haplotype was 54.8% in Indonesians and 39.9% in Caucasians (p<0.05). The frequency of the AAGGG haplotype was 14.3% in Indonesians and 29.3% in Caucasians. Moreover, there were significant differences in the frequencies of haplotype pairs between Indonesians and Caucasians (p<0.001). Indonesian cancer patients had significantly different AAGAG and AAGGG haplotype frequencies of the gene encoding the 5-HT3B receptor compared to healthy Caucasians. This finding could be useful for understanding interethnic differences in the response to drugs targeting the 5-HT3B receptor in cancer-treatment-related emesis.
    The International journal of biological markers 11/2011; 27(1):34-8. · 1.36 Impact Factor
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    ABSTRACT: The contribution of low-penetrance single nucleotide polymorphisms to methotrexate efficacy in rheumatoid arthritis (RA) is inconsistent between studies. We sought to elucidate architecture of methotrexate response in three cohorts of patients with RA treated with methotrexate. Single nucleotide polymorphism frequencies in genes from folate, purine, and pyrimidine pathways were measured to develop a model of gene-gene interactions using multifactor dimensionality reduction in 439 patients who received methotrexate in the USA and The Netherlands. A third cohort of 530 patients with RA from Sweden was used to replicate the findings. Methotrexate efficacy was assessed using the European League Against Rheumatism criteria in the majority of patients. Nonlinear patterns of gene-gene interactions between variants in aminoimidazole carboxamide ribonucleotide transformylase (C347G), reduced-folate carrier (G80A) and inosine-triphosphate pyrophosphatase (C94A) revealed a predisposing genetic attribute significantly associated with methotrexate response in the USA and Dutch cohorts [odds ratio (OR)=2.9, 95% confidence interval (CI): 1.9-4.2; P<0.001]. Although the finding was not replicated in the Swedish cohort (OR=0.9; 95% CI: 0.64-1.37; P=0.74) a multifactor dimensionality reduction analysis superimposing the predisposing genetic attribute with patient's age, sex, and anticitrullinated peptide antibodies positivity (ACPA) revealed a pattern of interaction significant in all three cohorts (OR=2.2, 95% CI: 1.6-2.9; P<0.01). The selective advantage toward response in the presence of the predisposing genetic attribute was lost in females and ACPA-positive patients, whereas older and male ACPA-negative patients tended to exhibit a greater likelihood of response in the absence of the predisposing genetic attribute. Gene-gene interactions together with nongenetic attributes may contribute to methotrexate efficacy in RA.
    Pharmacogenetics and Genomics 10/2011; 22(1):1-9. · 3.45 Impact Factor
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    ABSTRACT: Our purpose was to investigate the feasibility of pharmacy-initiated pharmacogenetic (PGt) screening in primary care with respect to patient willingness to participate, quality of DNA collection with saliva kits, genotyping, and dispensing data retrieved from the pharmacy. Polypharmacy patients aged >60 years who used at least one drug with Anatomical Therapeutic Chemical (ATC) code N06AA01-N06AX19 (antidepressants), A02BC01-A02BC05 (proton-pump inhibitors), N05AA01-N05AH04 (antipsychotics), or C07AB02 (metoprolol) in the preceding 2 years were randomly selected. DNA was collected with saliva kits and genotyped for CYP2D6 and CYP2C19 with the AmpliChip. Pharmacy dispensing records were retrieved and screened for drugs interacting with the patient's CYP2D6 and CYP2C19 genotype by using the evidence-based PGt guidelines from the Dutch Pharmacogenetics Working Group. Out of the 93 invited patients, 54 (58.1%) provided informed consent. Nine saliva samples (16.7%) contained too little DNA. Call rates for CYP2D6 and CYP2C19 were 93.3% and 100%, respectively. Frequencies of genotype-predicted phenotype were 2.4%, 38.1%, 54.8%, and 4.8% for CYP2D6 poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM), and ultrarapid metabolizers (UM) respectively. For CYP2C19 genotype-predicted phenotype, frequencies were 2.2%, 15.6%, and 82.2% for PM, IM, and EM, respectively. This study shows that pharmacy-initiated PGt screening is feasible for a primary care setting.
    European Journal of Clinical Pharmacology 10/2011; 68(4):363-70. · 2.70 Impact Factor
  • Clinical Cancer Research 09/2011; 17(17):5833-4; author reply 5835-6. · 8.19 Impact Factor
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    ABSTRACT: Suboptimal treatment of chemotherapy-induced nausea and vomiting and unsatisfactory response to antiemetic drugs cause impairment of cancer patient's daily functioning. This study was aimed to investigate the association of selected germline polymorphisms with ondansetron and metoclopramide response in Indonesian cancer patients treated with highly emetogenic chemotherapy. We enrolled 202 chemotherapy naïve patients treated with cisplatin at a dosage of ≥50 mg/m(2) as monotherapy or as combined chemotherapy. Ondansetron 8 mg and dexamethasone 8 mg intravenously were the standard antiemetic therapy for prevention of acute chemotherapy-induced nausea and vomiting. Metoclopramide 10 mg orally, three times per day as fixed prescription, was given until 5 days after chemotherapy to prevent delayed chemotherapy-induced nausea and vomiting. Primary and secondary outcomes were the occurrence of chemotherapy-induced nausea and vomiting in the acute and delayed phase. The following single-nucleotide polymorphisms were determined in ABCB1: rs1045642, rs2032582 and rs1128503; in 5-HT3B-R: rs45460698, rs4938058 and rs7943062; and in CYP2D6: rs16947 (CYP2D6 2), rs3892097 (CYP2D6 4) and rs1065852 (CYP2D6 10) using Taqman assays. During the acute phase, 21.8 and 30.2% patients experienced Grade 3 and 4 nausea and vomiting, respectively, whereas 38.6% patients experienced nausea and/or vomiting in the delayed phase. Carriers of the CTG haplotype of the ABCB1 gene experienced Grade 3 and 4 chemotherapy-induced nausea and vomiting more often than other haplotypes in the delayed phase (P< 0.05). No associations were found with the 5-HT3B receptor haplotypes and CYP2D6-predicted phenotypes. Our study shows that in Indonesian cancer patients treated with highly cytostatic emetogenic, carriership of the CTG haplotype of the ABCB1 gene is related to an increased risk of delayed chemotherapy-induced nausea and vomiting.
    Japanese Journal of Clinical Oncology 08/2011; 41(10):1168-76. · 1.75 Impact Factor
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    ABSTRACT: Pharmacogenetics is the search for heritable genetic polymorphisms that influence responses to drug therapy. The most important application of pharmacogenetics is to guide choosing agents with the greatest potential of efficacy and smallest risk of adverse drug reactions. Many studies focusing on drug-gene interactions have been published in recent years, some of which led to adaptation of FDA recommendations, indicating that we are on the verge of the clinical application of genetic information in drug therapy. This systematic review provides a comprehensive overview of the current knowledge on pharmacogenetics of all major drug classes currently used in the treatment of cardiovascular diseases.
    European Heart Journal 07/2011; 33(2):165-75. · 14.72 Impact Factor
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    ABSTRACT: Polymorphisms in CYP2C9 and VKORC1 influence patients' phenprocoumon (PHE) and acenocoumarol (ACE) dose requirements. To provide physicians with tools to estimate the patient's individual dose, we aimed to develop algorithms for PHE and ACE. In two Dutch anticoagulation clinics, data on age, sex, height, weight, co-medication, coumarin derivative doses, and international normalized ratio values were obtained from 624 patients taking PHE and 471 taking ACE. Single nucleotide polymorphisms relevant to coumarin derivative dosing on the CYP2C9 and VKORC1 genes were determined. Using multiple linear regression, we developed genotype-guided and non-genotype-guided algorithms to predict the maintenance dose with patient characteristics and genetic information. In addition, loading doses were derived from the calculated maintenance doses. We performed external validation in an independent data set with 229 PHE and 168 ACE users. CYP2C9 and VKORC1 genotype, weight, height, sex, age, and amiodarone use contributed to the maintenance dose of PHE and ACE. The genotype-guided algorithms explained 55.9% (PHE) and 52.6% (ACE) of the variance of the maintenance dose, the non-genetic algorithms 17.3% (PHE) and 23.7% (ACE). Validation in an independent data set resulted in an explained variation of 59.4% (PHE) and 49.0% (ACE) for the genotype-guided algorithms and for 23.5% (PHE) and 17.8% (ACE) for the non-genotype-guided algorithms, without height and weight as parameters. To our knowledge, these are the first genotype-guided loading and maintenance dose algorithms for PHE and ACE using large cohorts. The utility of these algorithms will be tested in randomized controlled trials.
    European Heart Journal 06/2011; 32(15):1909-17. · 14.72 Impact Factor
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    ABSTRACT: After the identification of type 2 diabetes mellitus (T2DM) risk alleles from genome-wide association studies, models have been developed to identify subjects at high risk to develop T2DM. We hypothesize that a panel of 20 repeatedly associated T2DM risk alleles influences response to sulfonylureas (SUs). Two hundred and seven incident SU (tolbutamide, glibenclamide, glimepiride, gliclazide) users with T2DM were recruited from four primary care centers. A genetic risk score per patient was calculated based on the number of risk-alleles. With this score, patients were categorized into three predefined genetic risk groups. The effect of the genetic risk group on the achievement of stable SU dose, prescribed stable SU dose, and time to stable SU dose was analyzed. Carriers of more than 17 T2DM risk alleles had a 1.7-fold reduced likelihood to achieve stable SU dose (P=0.044). No significant effect of the number of T2DM risk alleles on prescribed dose was found. Carriers of more than 17 T2DM risk alleles showed a marginally significant increased time to stable dose (hazard ratio: 0.81; 95% confidence interval, 0.75-1.01, P=0.058). T2DM risk alleles are associated with response to SUs in primary care T2DM patients. This suggests that individualization of T2DM treatment according to genetic profile may be an opportunity to improve clinical outcome.
    Pharmacogenetics and Genomics 05/2011; 21(8):461-8. · 3.45 Impact Factor
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    ABSTRACT: The objective of this study was to identify genetic polymorphisms related to the pharmacokinetics and pharmacodynamics of sunitinib that are associated with a prolonged progression-free survival (PFS) and/or overall survival (OS) in patients with clear-cell metastatic renal cell cancer (mRCC) treated with sunitinib. A retrospective multicenter pharmacogenetic association study was performed in 136 clear-cell mRCC patients treated with sunitinib. A total of 30 polymorphisms in 11 candidate genes, together with clinical characteristics were tested univariately for association with PFS as primary and OS as secondary outcome. Candidate variables with P < 0.1 were analyzed in a multivariate Cox regression model. Multivariate analysis showed that PFS was significantly improved when an A-allele was present in CYP3A5 6986A/G [hazard ratio (HR), 0.27; P = 0.032], a CAT copy was absent in the NR1I3 haplotype (5719C/T, 7738A/C, 7837T/G; HR, 1.76; P = 0.017) and a TCG copy was present in the ABCB1 haplotype (3435C/T, 1236C/T, 2677G/T; HR, 0.52; P = 0.033). Carriers with a favorable genetic profile (n = 95) had an improved PFS and OS as compared with noncarriers (median PFS and OS: 13.1 versus 7.5 months and 19.9 versus 12.3 months). Next to the genetic variants, the Memorial Sloan-Kettering Cancer Center prognostic criteria were associated with PFS and OS (HR, 1.99 and 2.27; P < 0.001). This exploratory study shows that genetic polymorphisms in three genes involved in sunitinib pharmacokinetics are associated with PFS in mRCC patients treated with this drug. These findings advocate prospective validation and further elucidation of these genetic determinants in relation to sunitinib exposure and efficacy.
    Clinical Cancer Research 02/2011; 17(3):620-9. · 8.19 Impact Factor

Publication Stats

769 Citations
234.70 Total Impact Points

Institutions

  • 2007–2013
    • Leiden University Medical Centre
      • • Department of Clinical Oncology
      • • Department of Clinical Pharmacy and Toxicology
      Leiden, South Holland, Netherlands
  • 2011
    • Universiteit Utrecht
      • Division of Pharmacoepidemiology and Pharmacotherapy
      Utrecht, Provincie Utrecht, Netherlands
    • Ahmad Dahlan University
      • Faculty of Pharmacy
      Jogjakarta, Daerah Istimewa Yogyakarta, Indonesia
    • VU University Medical Center
      Amsterdamo, North Holland, Netherlands
  • 2009
    • University Medical Center Utrecht
      Utrecht, Utrecht, Netherlands