Abstract PO-117: Population pharmacokinetics of vincristine and its metabolite in Kenyan pediatric cancer patients

Abstract

Abstract Purpose: Pharmacokinetic (PK) dispositions of vincristine (VCR) and its M1 metabolite were characterized through PK co-modeling for Kenyan pediatric cancer patients with acute lymphoblastic leukemia or nephroblastoma. VCR dosing strategies are largely empirical regardless of its extensive use in pediatric oncology. Little information is known about its disposition and optimal therapeutic dosing. Renbarger and associates reported that CYP3A5 enzyme metabolizes VCR to M1 more efficiently than CYP3A4 enzyme. This may be clinically significant as CYP3A5 expression varies among Kenyans (90%), African Americans (AA, 70%) and Caucasians (10-20%). Therefore, it is essential to characterize the disposition of M1 in humans to provide an insight into the inter-ethnic variability in VCR metabolism and clearance, which will be helpful for future dosing regimen optimization. Methods: Pharmacokinetic Study: Dried blood spot (DBS) samples were collected, via finger stick at various time points depending on the feasibility, from 25 Kenyan pediatric cancer patients (13 males/12 females, 1-14 years, BSA of 0.36 - 1.3 m2) after an IV dose of VCR (1.6 – 3.1 mg/m2). Concentrations of VCR and M1 from DBS were quantified using a validated LC-MS-MS assay. Pharmacokinetic Modeling: A population PK (pop PK) co-model was developed using Phoenix® NLMETM software to simultaneously capture and predict the PK of VCR and M1 concentrations. A correlation between the observed and predicted concentrations of VCR and M1 PK was established by pop PK fitting. Model discrimination was performed on data by visual inspection, the goodness of fit plots and AIC values. Results: The best fit pop PK co-model for VCR and its M1 metabolite was established. PK parameter estimates were derived for both analytes. Volumes of distribution for VCR and M1 were 0.12 L (33.55 %CV) and 249.07 L (33.42 %CV), respectively. The elimination rate constants for VCR and M1 were 5.6 hr-1 (22.81 %CV) and 0.00015 hr-1 (66.85 %CV), respectively. The conversion rate constant of VCR to M1 was 9.66 hr-1 (32.49 %CV). Finally, clearance values were 0.67 L/hr for VCR and 0.04 L/hr for M1. In conclusion, VCR and its M1 metabolite exhibit distinct PK characteristics, in that M1 distribution is substantially larger than that of VCR (249 vs 0.12 L), and clearance is slower than that of VCR (0.04 vs 0.67 L/hr). The conversion kinetics of VCR to M1 is characterized for the first time, which may potentially offer a rationale for ethnic disparity in VCR therapy. In addition, a large inter-patient variability is documented even within the same ethnic Kenyan population. After model refinement and validation, our model could potentially serve as a tool for rational VCR dosing regimen modification for Kenyan/AA pediatric cancer patients. Citation Format: Lorita Agu, Lei Wu, Jamie Renbarger, Jodi Skiles, Andi Masters, Diana S-L. Chow. Population pharmacokinetics of vincristine and its metabolite in Kenyan pediatric cancer patients [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-117.