Abstract
Background The antimalarial drug amodiaquine, a commonly used long acting partner drug in artemisinin-based combination therapy, is metabolized to active desethyl-amodiaquine (DEAQ) by cytochrome P450 2C8 (CYP2C8). The CYP2C8 gene carries several polymorphisms including the more frequent minor alleles CYP2C8*2 and CYP2C8*3. These minor alleles have been associated with decreased enzymatic activity, slowing the amodiaquine biotransformation towards DEAQ. This study aimed to assess the influence of CYP2C8 polymorphisms on the efficacy and tolerability of artesunate-amodiaquine treatment for uncomplicated Plasmodium falciparum malaria in Zanzibar.Methods We analysed data from 618 children <5 years with uncomplicated P. falciparum malaria enrolled in two randomized clinical trials comparing artesunate-amodiaquine and artemether-lumefantrine in 2002-2005 in Zanzibar. CYP2C8*2 and CYP2C8*3 genotypes were determined by PCR-restriction fragment length polymorphism and assessed in relation to clinical data on treatment outcome and tolerance. Results The allele frequencies of CYP2C8*2 and CYP2C8*3 were 17.5% (95% CI 15.4-19.7%) and 2.7% (95% CI 1.8-3.7%), respectively. There was no significant difference in the proportion of subjects carrying either CYP2C8*2 or CYP2C8*3 alleles amongst those with reinfections (44.1 %; 95% CI 33.8-54.8) or those with recrudescent infections (48.3%; 95% CI 29.4-67.5), compared to those with adequate clinical and parasitological response (36.7 %; 95% CI 30.0-43.9) (P = 0.25 and P = 0.31, respectively). However, patients carrying either the CYP2C8*2 or CYP2C8*3 allele were significantly associated with increased occurrence of non-serious adverse events compare with CYP2C8 *1/*1 wildtype homozygotes (44.9%; 95% CI 36.1-54.0 versus 28.1%; 95% CI 21.9-35.0, respectively; P = 0.003). Conclusions CYP2C8 genotypes did not influence treatment efficacy directly, but the tolerability to ASAQ may be reduced in subjects carrying the CYP2C8*3 and CYP2C8*2 alleles. The importance of this non-negligible association with regards to amodiaquine-based malaria chemotherapy warrants further investigation.
Cytochrome P450 2C8
