Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Studies Related to Vincristine-Induced Peripheral Neuropathy in Chinese Pediatric ALL Patients.

Abstract

Vincristine (VCR) can cause vincristine-induced peripheral neuropathy (VIPN) during the treatment of acute lymphoblastic leukemia (ALL) and the mechanisms are complicated. The aim of this study was to investigate the influencing factors on the population pharmacokinetics (PopPK) and pharmacodynamics (PD) related to VIPN, including clearance routes, drug-drug interactions (DDI), and genetic characteristics. Pediatric patients being treated for ALL were recruited to PK study where VCR and its metabolite (M1) were measured using a novel assay. The incidence of VIPN was also recorded. DNA sequencing of relevant PK and PD genes was performed. PopPK and PK/PD models were developed, pharmacogenetic and DDI analyses were conducted. In total, 79 children were recruited. The results showed that allometric scaling, ABCB1-rs1128503 genotype, and posaconazole (POS) significantly improved the PopPK model fit. VIPN was significantly correlated with the exposure of VCR. Co-administration with POS shifted the effect curve for VIPN to the left, indicating increased VIPN risk at the same exposure levels. No significant effects on VIPN were observed for CYP3A5 (rs776746), CYP3A4 (rs2242480), CEP72 (rs924607), or various ABCB1 variants (rs1128503, rs2032582, rs1045642, rs4728709, rs4148737, and rs10276036), nor with the co-administration of fluconazole or dasatinib. In summary, co-administration of POS increased VCR exposure by 0.4-fold and raised the risk of VIPN, with an occurrence probability generally exceeding 0.7. Therapeutic drug monitoring of VCR in clinical practice may be necessary to enable appropriate dose adjustments and individualized treatment.