The effect of single nucleotide polymorphisms in cytochrome P450 isoenzyme and N-acetyltransferase-2 genes on the metabolism of artemisinin-based combination therapies in malaria patients from Cambodia and Tanzania

The pharmacogenetics of antimalarials is poorly known, although its application might be critical to optimize treatment. This population pharmacokinetic-pharmacogenetic study aimed at assessing the effect of single nucleotide polymorphisms (SNPs) in cytochrome P450 isoenzyme (CYP, namely CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5) and N-acetyltransferase-2 (NAT2) genes on the pharmacokinetics of artemisinin-based combination therapies (ACT) in 150 Tanzanian patients treated with artemether-lumefantrine, 64 Cambodian patients treated with artesunate-mefloquine, and 61 Cambodian patients treated with dihydroartemisinin-piperaquine. The frequency of SNPs varied with the enzyme and the population. Higher frequencies of mutant alleles were found in Cambodians than Tanzanians for CYP2C9*3, CYP2D6*10 (100C<T), CYP3A5*3, NAT2*6, and NAT2*7. In contrast, higher frequencies of mutant alleles were found in Tanzanians for CYP2D6*17 (1023C<T and 2850C<T), CYP3A4*1B, NAT2*5, and NAT2*14. In 8 SNPs no significant differences in frequencies were observed. In the genetic-based population pharmacokinetic analyses, none of the SNPs improved model fit. This suggests that pharmacogenetic data need not be included in appropriate first-line treatments with the current artemisinin derivatives and quinolines for uncomplicated malaria in specific populations. However, it cannot be ruled out that our results represent isolated findings, and therefore more studies, ideally with the same artemisinin-based combination therapies, in different populations are needed to evaluate the influence of pharmacogenetic factors on the clearance of antimalarials