title: Population pharmacokinetics and pharmacogenetics of vincristine in paediatric patients treated for solid tumour diseases.
abstract: OBJECTIVE
  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.
authors.affiliation: Inserm U911, Faculté de Pharmacie, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 5, France. romain.guilhaumou@ap-hm.fr
authors.forename: Romain
authors.initials: R
authors.lastname: Guilhaumou
authors.forename: Nicolas
authors.initials: N
authors.lastname: Simon
authors.forename: Sylvie
authors.initials: S
authors.lastname: Quaranta
authors.forename: Arnauld
authors.initials: A
authors.lastname: Verschuur
authors.forename: Bruno
authors.initials: B
authors.lastname: Lacarelle
authors.forename: Nicolas
authors.initials: N
authors.lastname: Andre
authors.forename: Caroline
authors.initials: C
authors.lastname: Solas
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000293:Adolescent; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D014750:Vincristine / Q000493:pharmacokinetics*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D014750:Vincristine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human