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Pharmacogenetic Screening of CYP3A and ABCB1 in Relation to Population Pharmacokinetics of Docetaxel

Authors' Affiliations: ¹ Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital; ² Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute; ³ Department of Internal Medicine, Slotervaart Hospital, Amsterdam, the Netherlands; ⁴ Department of Internal Medicine, Section of Oncology, University Medical Center Utrecht; ⁵ Department of Biomedical Analysis, Faculty of Pharmaceutical Sciences, University of Utrecht, Utrecht, the Netherlands; ⁶ Department of Internal Medicine, Section of Oncology and Haematology, Medical Spectrum Twente, Enschede, the Netherlands; ⁷ Department of Internal Medicine, Section of Oncology, University Hospital, Maastricht, the Netherlands; and ⁸ Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands

Requests for reprints: Tessa M. Bosch, Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, the Netherlands. Phone: 31-20-512-4657; Fax: 31-20-512-4753; E-mail: aptbo{at}slz.nl.

Purpose: Despite the extensive clinical experience with docetaxel, unpredictable interindividual variability in efficacy and toxicity remain important limitations associated with the use of this anticancer drug. Large interindividual pharmacokinetic variability has been associated with variation in toxicity profiles. Genetic polymorphisms in drug-metabolizing enzymes and drug transporters could possibly explain the observed pharmacokinetic variability. The aim of this study was therefore to investigate the influence of polymorphisms in the CYP3A and ABCB1 genes on the population pharmacokinetics of docetaxel.

Experimental Design: Whole blood samples were obtained from patients with solid tumors and treated with docetaxel to quantify the exposure to docetaxel. DNA was collected to determine polymorphisms in the CYP3A and ABCB1 genes with DNA sequencing. A population pharmacokinetic analysis of docetaxel was done using nonlinear mixed-effect modeling.

Results: In total, 92 patients were assessable for pharmacokinetic analysis of docetaxel. A three-compartmental model adequately described the pharmacokinetics of docetaxel. Several polymorphisms in the CYP3A and ABCB1 genes were found, with allele frequencies of 0.54% to 48.4%. The homozygous C1236T polymorphism in the ABCB1 gene (ABCB1*8) was significantly correlated with a decreased docetaxel clearance (–25%; P = 0.0039). No other relationships between polymorphisms and pharmacokinetic variables reached statistical significance. Furthermore, no relationship between haplotypes of CYP3A and ABCB1 and the pharmacokinetics could be identified.

Conclusions: The polymorphism C1236T in the ABCB1 gene was significantly related to docetaxel clearance. Our current finding may provide a meaningful tool to explain interindividual differences in docetaxel treatment in daily practice.

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