1667P - Influence of drug exposure and genetic variation on paclitaxel-induced neurotoxicity

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Complications of Treatment
Presenter Anne-Joy De Graan
Authors A.M. De Graan1, L. Elens2, A. Sparreboom3, L.E. Friberg4, B. van der Holt5, P. De Raaf1, E.A.C. Wiemer6, R.H. van Schaik2, J. Verweij7, R. Mathijssen6
  • 1Medical Oncology, Erasmus MC, 3008AE - Rotterdam/NL
  • 2Clinical Chemistry, Erasmus MC, Rotterdam/NL
  • 3Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis/US
  • 4Pharmaceutical Biosciences, Uppsala University, Uppsala/SE
  • 5Trials And Statistics, Erasmus MC, Rotterdam/NL
  • 6Medical Oncology, Erasmus MC, Rotterdam/NL
  • 7Dept. Of Medical Oncology, Erasmus MC, Rotterdam/NL

Abstract

Objectives

Paclitaxel is used for the treatment of several solid tumors and displays a high inter-individual variation in exposure and toxicity. Neurotoxicity is a frequent and sometimes serious adverse event frequently of paclitaxel treatment. This study aims to find predictive pharmacokinetic (PK) and pharmacogenetic determinants for the development of neurotoxicity.

Methods

In 261 patients treated with paclitaxel, incidence of neurotoxicity during all courses (according to CTC 4.0 criteria) and PK parameters were determined. PK samples were measured by HPLC or LC-MS/MS, and individual PK parameters were estimated from previously developed population PK models by non-linear mixed effects modeling in the software NONMEM. Univariate and multivariate stepwise regression analysis were used to study the influence of co-variables on the development of neurotoxicity. Variables tested were age, dose, tumor type, ethnicity, co-medication, smoking status, and genetic variants in the PK-pathway of paclitaxel (CYP3A4*22, CYP3A5*3, CYP2C8*3, CYP2C8 rs1058932, and ABCB1 3435 C > T, determined by TaqMan genotyping assays on the ABI PRISM 7500 Fast real-time PCR System).

Results

Exposure to paclitaxel (logAUC) was predictive for the development (P<0.00001) and severity of neurotoxicity (P <0.00001). Patients without neurotoxicity, grade 1 neurotoxicity, grade 2 or grade 3 neurotoxicity had a median paclitaxel AUC of 3.24, 12.51, 13.46 and 16.45 ng × h/mL, respectively. In multivariate analysis, independent predictive factors for development of neurotoxicity were higher logAUC (P = 0.021), female gender (P = 0.008), and CYP3A4*22 carrier status (P = 0.014). Female carriers of the decreased function allele CYP3A4*22 had increased risk of developing neurotoxicity (P = 0.004), whereas male carriers had not.

Conclusions

This is the first large study showing a clear relationship between paclitaxel exposure and development of drug-induced neurotoxicity in paclitaxel-treated patients. Female CYP3A4*22 carriers have a higher incidence of neurotoxicity during paclitaxel therapy. These observations may contribute to the further individualization of paclitaxel treatment.

Disclosure

All authors have declared no conflicts of interest.