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Medline ® Abstract for Reference 82

of 'Overview of neurologic complications of non-platinum cancer chemotherapy'

CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity.
de Graan AJ, Elens L, Sprowl JA, Sparreboom A, Friberg LE, van der Holt B, de Raaf PJ, de Bruijn P, Engels FK, Eskens FA, Wiemer EA, Verweij J, Mathijssen RH, van Schaik RH
Clin Cancer Res. 2013;19(12):3316. Epub 2013 May 2.
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.
Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, the Netherlands.