Abstract 2801: Pharmacokinetic modeling of Vincristine and its metabolite in Kenyan pediatric cancer patients
Authors: Cornett Taylor , Agu Lorita , Wu Lei , Dai Lu , Skiles Jodi L. , Masters Andrea R. , Renbarger Jamie L. , Chow Diana Shu-Lian 
Published: April 2023

Abstract
This feasibility study aimed to establish the logistically feasible protocol for the Phase I trial in Kenyan pediatric cancer patients. The trial’s ultimate goal is to rationally optimize the dosing of the anti-cancer drug, Vincristine (VCR).
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 (77) Kenyan pediatric cancer patients (37M/40F, 1-16 yo, BSA of 0.38-1.64 m2) with 9 types of cancers, Acute Lymphoblastic Leukemia (ALL, N=28), and Non-Hodgkin’s Lymphoma (NHL, N=21), Hodgkin's Lymphoma (HL, N=5), Wilm’s Tumor (WT/NEPHRO, N=13), Retinoblastoma (RETINO, N=5), Rhabdomyosarcoma (RMS, N=2), Hepatoma (HEPATO, N=1), Teratoma (TERA, N=1), and Neuroblastoma (NEURO, N=1) 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. Concentrations were quantified for VCR and M1 using a validated LC-MS/MS assay with LLOQ of 0.6 ng/ml for VCR and 0.4 ng/ml for M1. 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. The VCR to M1 conversion was active in 38-42% of subjects yielding higher M1 than VCR in plasma profiles. The conversion kinetics in k12 ranged from &lt; 0.01 to 44 hr-1. The mean k12 among WT, ALL, and NHL patients were 4.27+6.31, 5.83+13.00, and 1.98+3.31 hr-1, respectively. The elimination rate constants of VCR and M1 were characterized as 3.89+9.19 and 8.37+21.84 in the WT group, 1.75+4.44 and 17.75+26.37 in the ALL group, and 2.17+7.68 and 19.41+31.45 in the NHL group. The covariate analyses with age, sex, and type of cancer did not further improve the AIC values of the model.
In conclusion, the feasibility study demonstrated that the current clinical protocol is suitable for the Phase 1 trial. The quantification of the limited blood sample volume on DBS was overcome by the reproducible extraction and sensitive LC-MS/MS assay method. 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 Vincristine and M1 for individual subjects among the various types of tested cancers.
Citation Format: Taylor Cornett, Lorita Agu, Lei Wu, Lu Dai, Jodi L. Skiles, Andrea R. Masters, Jamie L. Renbarger, Diana Shu-Lian Chow. Pharmacokinetic modeling of Vincristine and its metabolite in Kenyan pediatric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2801.