Evaluation of 5-Fluorouracil Pharmacokinetics in Cancer Patients with a c.1905+1G > A Mutation in DPYD by Means of a Bayesian Limited Sampling Strategy

Autor: Kati Jabschinsky, Andreas Schalhorn, Peter Häusler, J. G. Maring, André B.P. van Kuilenburg, Johannes H. Proost, Michael W.T. Tanck, Wolfgang Schwabe, Christoph Terborg, D. Behnke
Přispěvatelé: Nanomedicine & Drug Targeting, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, CCA -Cancer Center Amsterdam, Laboratory Genetic Metabolic Diseases, APH - Amsterdam Public Health, Epidemiology and Data Science
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Male
Dihydropyrimidine Dehydrogenase Deficiency
Pharmacology
Gastroenterology
COLORECTAL-CANCER
Dihydropyrimidine dehydrogenase deficiency
Neoplasms
Pharmacology (medical)
Biotransformation
Netherlands
education.field_of_study
Middle Aged
DONOR SITE
Phenotype
Fluorouracil
Toxicity
SINGLE NUCLEOTIDE POLYMORPHISMS
Female
Drug Monitoring
medicine.drug
Adult
Antimetabolites
Antineoplastic
Heterozygote
medicine.medical_specialty
SEVERE TOXICITY
Metabolic Clearance Rate
Population
Models
Biological
Pharmacokinetics
Internal medicine
medicine
Dihydropyrimidine dehydrogenase
Humans
DIHYDROPYRIMIDINE DEHYDROGENASE-DEFICIENCY
education
IVS14+1G-GREATER-THAN-A MUTATION
Dihydrouracil Dehydrogenase (NADP)
Aged
Retrospective Studies
DPD DEFICIENCY
business.industry
Bayes Theorem
medicine.disease
GENE
POINT MUTATION
FLUOROURACIL
Logistic Models
ROC Curve
Pharmacogenetics
Mutation
Linear Models
DPYD
business
Zdroj: Clinical Pharmacokinetics, 51(3), 163-174. Springer International Publishing AG
Clinical pharmacokinetics, 51(3), 163-174. Adis International Ltd
ISSN: 0312-5963
Popis: Background and Objective: Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme in the catabolism of 5-fluorouracil (5FU) and DPD deficiency is an important pharmacogenetic syndrome. So far, only very limited information is available regarding the pharmacokinetics of 5FU in patients with a (partial) DPD deficiency and no limited sampling models have been developed taking into account the non-linear pharmacokinetic behaviour of 5FU. The aim of this study was to evaluate the pharmacokinetics of 5FU and to develop a limited sampling strategy to detect decreased 5FU elimination in patients with a c.1905+1G>A-related DPD deficiency. Methods: Thirty patients, heterozygous for the c.1905+1G>A mutation in DPYD, and 18 control patients received a dose of 5FU 300 mg/m(2) and/or 5FU 450 mg/m(2), followed by pharmacokinetic analysis of the 5FU plasma levels. A population pharmacokinetic analysis was performed in order to develop a compartmental pharmacokinetic model suitable for a limited sampling strategy. Clinical aspects of treating DPD-deficient patients with 5FU-based chemotherapy were assessed from the retrospectively collected clinical data. Results: In a two-compartment model with Michaelis-Menten elimination, the mean maximum enzymatic conversion capacity (V-max) value was 40% lower in DPD-deficient patients compared with controls (p
Databáze: OpenAIRE
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