title: Impact of plasma and intracellular exposure and CYP3A4, CYP3A5, and ABCB1 genetic polymorphisms on vincristine-induced neurotoxicity.
abstract: OBJECTIVE
  The aim of this study was to investigate the impact of plasma and intracellular exposure and CYP3A4, CYP3A5, and ABCB1 polymorphisms on vincristine neurotoxicity. We subsequently assessed the impact of ABCB1 polymorphisms on intracellular vincristine accumulation.
  
  
  METHODS
  Children treated for solid tumors were enrolled in the study (n = 26) and received 1.5 mg/m² of vincristine per course. Individual pharmacokinetic parameters and CYP3A4, CYP3A5, and ABCB1 genotypes were available from a previous analysis. A global toxicity score (pain, peripheral neurotoxicity, and gastrointestinal toxicity) was collected at each course. Vincristine in plasma and PBMCs were quantified by LC-MS/MS.
  
  
  RESULTS
  Vincristine plasma and intracellular concentrations ranged from 0.40 to 89.6 ng/ml and from 0.00225 to 1.85 ng/10(6) cells over a 24-h interval, respectively. The global toxicity score ranged from 0 to 6 and was not correlated with individual pharmacokinetics parameters. Neurotoxicity events (global score ≥ 3) were observed in 8 patients but the incidence was not influenced by the different studied polymorphisms. The global toxicity score was correlated with age, body surface area, and dose in mg. A trend to higher intracellular/plasma ratio of vincristine was found for patients with heterozygous diplotype (CGC-TTT) of ABCB1.
  
  
  CONCLUSIONS
  None of the different genetic covariates nor plasma and intracellular exposure was predictive of the observed neurotoxicity in our pediatric population. Nevertheless, the heterozygote diplotype of ABCB1 appears to influence the intracellular accumulation of vincristine. Owing to the small sample size, further evaluations are needed in a larger patient cohort.
authors.affiliation: Aix-Marseille Univ, CRO2, INSERM, UMR 911, 13385 Marseille, France. romain.guilhaumou@ap-hm.fr
authors.forename: Romain
authors.initials: R
authors.lastname: Guilhaumou
authors.forename: Caroline
authors.initials: C
authors.lastname: Solas
authors.forename: Veronique
authors.initials: V
authors.lastname: Bourgarel-Rey
authors.forename: Sylvie
authors.initials: S
authors.lastname: Quaranta
authors.forename: Angelique
authors.initials: A
authors.lastname: Rome
authors.forename: Nicolas
authors.initials: N
authors.lastname: Simon
authors.forename: Bruno
authors.initials: B
authors.lastname: Lacarelle
authors.forename: Nicolas
authors.initials: N
authors.lastname: Andre
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 / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D011110:Polymorphism, Genetic; D014750:Vincristine / Q000009:adverse effects* / Q000097:blood
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