Impact of pharmacogenetics on variability in exposure to oral vinorelbine among pediatric patients: a model-based population pharmacokinetic analysis

Abstract

Purpose: Better understanding of pharmacokinetics of oral vinorelbine (VNR) in children would help predicting drug exposure and, beyond, clinical outcome. Here, we have characterized the population pharmacokinetics of oral VNR and studied the factors likely to explain the variability observed in VNR exposure among young patients.

Design/methods: We collected blood samples from 36 patients (mean age 11.6 years) of the OVIMA multicentric phase II study in children with recurrent/progressive low-grade glioma. Patients received 60 mg/m² of oral VNR on days 1, 8, and 15 during the first 28-day treatment cycle and 80 mg/m², unless contraindicated, from cycle 2-12. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling within the Monolix^® software. Fifty SNPs of pharmacokinetic-related genes were genotyped. The influence of demographic, biological, and pharmacogenetic covariates on pharmacokinetic parameters was investigated using a stepwise multivariate procedure.

Results: A three-compartment model, with a delayed double zero-order absorption and a first-order elimination, best described VNR pharmacokinetics in children. Typical population estimates for the apparent central volume of distribution (V_c/F) and elimination rate constant were 803 L and 0.60 h^-1, respectively. Following covariate analysis, BSA, leukocytes count, and drug transport ABCB1-rs2032582 SNP showed a dramatic impact on V_c/F. Conversely, age and sex had no significant effect on VNR pharmacokinetics.

Conclusion: Beyond canonical BSA and leukocytes, ABCB1-rs2032582 polymorphism showed a meaningful impact on VNR systemic exposure. Simulations showed that the identified covariates could have an impact on both efficacy and toxicity outcomes. Thus, a personalized dosing strategy, using those covariates, could help to optimize the efficacy/toxicity balance of VNR in children.

Keywords: ABCB1; P-glycoprotein; Pediatric drug development; Population pharmacokinetic analysis; Vinorelbine.