CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity

Anne-joy Graan, Laure Elens, JA Sprowl, A Sparreboom, LE Friberg, Ronnie van der Holt, Johan Raaf, Peter de Bruijn, Frederike Engels, Ferry Eskens, Erik Wiemer, Jaap Verweij, RHJ Mathijssen, Ron van Schaik*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

95 Citations (Scopus)

Abstract

PURPOSE: Paclitaxel is used for the treatment of several solid tumors and displays a high interindividual variation in exposure and toxicity. Neurotoxicity is one of the most prominent side effects of paclitaxel. This study explores potential predictive pharmacokinetic and pharmacogenetic determinants for the onset and severity of neurotoxicity.

EXPERIMENTAL DESIGN: In an exploratory cohort of patients (n = 261) treated with paclitaxel, neurotoxicity incidence, and severity, pharmacokinetic parameters and pharmacogenetic variants were determined. Paclitaxel plasma concentrations were measured by high-performance liquid chromatography or liquid chromatography/tandem mass spectrometry, and individual pharmacokinetic parameters were estimated from previously developed population pharmacokinetic models by nonlinear mixed effects modeling. Genetic variants of paclitaxel pharmacokinetics tested were CYP3A4*22, CYP2C8*3, CYP2C8*4, and ABCB1 3435 C>T. The association between CYP3A4*22 and neurotoxicity observed in the exploratory cohort was validated in an independent patient cohort (n = 239).

RESULTS: Exposure to paclitaxel (logAUC) was correlated with severity of neurotoxicity (P < 0.00001). Female CYP3A4*22 carriers were at increased risk of developing neurotoxicity (P = 0.043) in the exploratory cohort. CYP3A4*22 carrier status itself was not associated with pharmacokinetic parameters (CL, AUC, Cmax, or T>0.05) of paclitaxel in males or females. Other genetic variants displayed no association with neurotoxicity. In the subsequent independent validation cohort, CYP3A4*22 carriers were at risk of developing grade 3 neurotoxicity (OR = 19.1; P = 0.001).

CONCLUSIONS: Paclitaxel exposure showed a relationship with the severity of paclitaxel-induced neurotoxicity. In this study, female CYP3A4*22 carriers had increased risk of developing severe neurotoxicity during paclitaxel therapy. These observations may guide future individualization of paclitaxel treatment.

Original languageEnglish
Pages (from-to)3316-3324
Number of pages9
JournalClinical Cancer Research
Volume19
Issue number12
DOIs
Publication statusPublished - 15 Jun 2013

Research programs

  • EMC MM-01-25-01
  • EMC MM-03-86-08
  • EMC OR-01-34-01

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