Pharmacokinetic Modeling of Vincristine and Its Metabolite in Kenyan Pediatric Cancer Patients

The CYP3A5 enzyme more efficiently metabolizes VCR to its M1 metabolite than the CYP3A4 enzyme as reported by Renbarger. CYP3A5 expression varies among Kenyans (90%), African Americans (AA, 70%), and Caucasians (10-20%). In order to dose the patients rationally among the different ethnicities, the pre-requisite is to comprehensively understand the pharmacokinetic (PK) disposition of VCR and M1, as well as the conversion kinetics from VCR to M1. Seventy-seven Kenyan pediatric cancer patients with 9 types of cancers, Acute Lymphoblastic Leukemia, Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, Wilm's Tumor, Retinoblastoma, Rhabdomyosarcoma, Hepatoma, Teratoma, and Neuroblastoma were recruited. Dried blood spot (DBS) samples of the Kenyan pediatric patients after an IV dose of VCR (0.9-2.2 mg/m2) were collected via finger stick at various time points depending on the feasibility. The PK co-models of VCR and M1 metabolite were developed, and PK parameters were derived for individual subjects. Using Phoenix NLME 8.0, model discrimination was performed by minimizing the Akaike Information Criteria (AIC) values and visual comparisons of the quality of fitness of the plots. The PK parameters were derived from the best fit Pk model. Large interpatient variability was observed. In conclusion, the feasibility study demonstrated that the current clinical protocol is suitable for the Phase 1 trial. In addition, the establishment of the PK co-models with Vincristine and M1 metabolite enables the derivation of conversion rate constant from VCR to M1 and elimination kinetics of VCR and M1 for individual subjects among the various types of tested cancers. ***This project was completed with contributions from Lorita Agu from Syntarat, Lei Wu from AbbVie Pharmaceuticals, and Jodi L. Skiles, Andrea R. Master, and Jamie L. Renbarger from the Indiana University School of Medicine.