Pharmacogenetic screening of CYP3A and ABCB1 in relation to population pharmacokinetics of docetaxel

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Published on: September 8, 2017

Tessa M Bosch1, Alwin D R Huitema, Valerie D Doodeman

  • 1Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, the Netherlands. aptbo@slz.nl

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|October 6, 2006
PubMed
Abstract

Insights

Genetic variations in the ABCB1 gene, specifically the C1236T polymorphism, significantly impact docetaxel clearance. This finding helps explain individual differences in docetaxel treatment response and toxicity.

Area of Science:

  • Pharmacogenomics
  • Oncology
  • Drug Metabolism

Background:

  • Docetaxel efficacy and toxicity show significant interindividual variability.
  • Pharmacokinetic variability is linked to toxicity profiles.
  • Genetic polymorphisms in drug-metabolizing enzymes and transporters may explain pharmacokinetic variability.

Purpose of the Study:

  • To investigate the influence of CYP3A and ABCB1 gene polymorphisms on docetaxel population pharmacokinetics.
  • To identify genetic markers associated with docetaxel variability.

Main Methods:

  • Population pharmacokinetic analysis of docetaxel using nonlinear mixed-effect modeling.
  • DNA sequencing to determine CYP3A and ABCB1 gene polymorphisms in 92 patients.
  • Whole blood samples analyzed for docetaxel exposure.

Main Results:

  • A three-compartmental model described docetaxel pharmacokinetics.
  • The ABCB1 C1236T polymorphism (homozygous) was significantly associated with decreased docetaxel clearance (-25%, P=0.0039).
  • No other significant relationships were found between polymorphisms or haplotypes and docetaxel pharmacokinetics.

Conclusions:

  • The ABCB1 C1236T polymorphism is a significant determinant of docetaxel clearance.
  • This finding offers a potential tool for personalizing docetaxel treatment and managing interindividual variability.

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