Population pharmacokinetics and pharmacogenetics of vincristine in paediatric patients treated for solid tumour diseases.

PURPOSE: The interindividual variability of vincristine pharmacokinetics is quite large, but the origins of this variability are not properly understood. The aim of this study was to develop a population pharmacokinetic model of vincristine in a paediatric population treated for solid tumour disease and evaluate the impact of different ABCB1, CYP3A4 and CYP3A5 polymorphisms on the different pharmacokinetic parameters.
METHODS: We assessed vincristine pharmacokinetics in 26 children treated for various solid tumour diseases. Genotypes were determined by real-time PCR with a LightCycler™ and ABCB1 haplotypes calculated using the software program Phase 2.1. Vincristine plasma concentrations were determined by LC-MS/MS, and a population approach was performed on 184 samples by the NONMEM computer program. Demographic, therapeutic and genotypic covariables were evaluated on vincristine pharmacokinetic parameters.
RESULTS: The frequency of CYP3A4*1A/*1A and *1A/*1B genotypes were 87.5 and 12.5%, respectively. CYP3A5*1/*3 and *3/*3 were observed in 20.8 and 79.2% of the patients, respectively. The three major haplotypes were (allelic frequencies) CGC (50%), CGT (14.6%) and TTT (23.2%). Vincristine pharmacokinetics was well described by a two-compartment model. Large interindividual and interoccasion variability were observed. The different polymorphisms studied did not improve the model prediction.
CONCLUSIONS: CYP3A4, CYP3A5 and ABCB1 polymorphisms did not significantly affect in vivo vincristine pharmacokinetics. Our results demonstrate that vincristine pharmacokinetic variability cannot be explained by these genetic polymorphisms.