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

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Abstract

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.

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Acknowledgments

This work was supported by a grant from Assistance Publique-Hôpitaux de Marseille.

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Authors and Affiliations

  1. Inserm U911, Faculté de Pharmacie, 27 Boulevard Jean Moulin, 13385, Marseille Cedex 5, France

    Romain Guilhaumou, Bruno Lacarelle, Nicolas Andre & Caroline Solas

  2. Laboratoire de Pharmacocinétique et Toxicologie, Hôpital de la Timone, 264 rue Saint Pierre, 13385, Marseille Cedex 5, France

    Romain Guilhaumou, Sylvie Quaranta, Bruno Lacarelle & Caroline Solas

  3. Laboratoire de Pharmacologie Médicale et Clinique, Hôpital de la Timone, 264 rue Saint Pierre, 13385, Marseille Cedex 5, France

    Nicolas Simon

  4. Service d’Oncologie Pédiatrique, Hôpital de la Timone, 264 rue Saint Pierre, 13385, Marseille Cedex 5, France

    Arnauld Verschuur & Nicolas Andre

Authors
  1. Romain Guilhaumou
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  2. Nicolas Simon
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Correspondence to Romain Guilhaumou.

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Guilhaumou, R., Simon, N., Quaranta, S. et al. Population pharmacokinetics and pharmacogenetics of vincristine in paediatric patients treated for solid tumour diseases. Cancer Chemother Pharmacol 68, 1191–1198 (2011). https://doi.org/10.1007/s00280-010-1541-4

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  • DOI: https://doi.org/10.1007/s00280-010-1541-4

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