Impact of Genetic Variation in Metabolic Enzymes on Treatment of Paclitaxel in the Rwandan Population

Abstract

Differences in genotypes encoding drug-metabolizing enzymes can lead to variability in both drug response and toxicity. These genotypes vary across geographical regions and ethnic groups, especially in African populations. In general, African populations are underrepresented in clinical trials. This study aimed to determine the allele frequencies of CYP2C8, CYP2C9, CYP2C19, and CYP1B1 in the Rwandan population; to explore potential clinical impact on toxicity of the CYP2C8*2 variant on paclitaxel metabolism and the need for genotype-based dosing using a population pharmacokinetic model. Genotyping was performed on DNA extracted from blood samples obtained from 82 Rwandan patients. Paclitaxel plasma concentrations for the different CYP2C8 genotypes were simulated based on available in vitro metabolism data and a population pharmacokinetic model. Toxicity was assessed as time above plasma concentration thresholds (>0.05 and 0.1 μM), and genotype-based dose regimens were simulated. The frequencies of the polymorphic alleles in the Rwandan population were 21%, 0.6%, 1.8%, 24%, and 26% for CYP2C8*2, CYP2C9*2, CYP2C19*3, CYP2C19*17, and CYP1B1, respectively. Simulations showed that CYP2C8*2 carriers spent approximately 1.7-fold and 1.9-fold longer above paclitaxel toxicity thresholds of 0.05 and 0.1 μM, respectively, than wild-type individuals. A dose of 100 mg/m² in CYP2C8*2 carriers produced exposure comparable to 175 mg/m² in wild-type individuals. The relatively high prevalence of CYP2C8*2 in the Rwandan population suggests potential clinical relevance for paclitaxel treatment. CYP2C8*2 may influence paclitaxel exposure and support genotype-guided dose reduction to improve treatment safety.