Distribution of the cytochrome P450 CYP2C8*2 allele in Brazzaville, Republic of Congo

Abstract

Background: Cytochrome P450 (CYP) enzymes are essential in the metabolism of most drugs used today. Single nucleotide polymorphism(s) occurring in CYP genes can adversely affect drug pharmacokinetics, efficacy, and safety. Individuals carrying the CYP2C8*2 c.805A > T (CYP2C8*2; rs11572103) allele have impaired amodiaquine metabolism, increased risk of amodiaquine-related adverse events, and may promote the selection of drug-resistant parasite strains. This study investigated the distribution of the CYP2C8*2 allele in Brazzaville, Republic of Congo, where artesunate + amodiaquine is used as the secondline treatment for uncomplicated Plasmodium falciparum malaria. Methods: A total of 285 febrile children visiting the Marien Ngouabi paediatric hospital were genotyped for CYP2C8*2 using PCR-restriction fragment length polymorphism (PCR-RFLP). The allele frequencies and genotype distribution were determined. Results: The CYP2C8*2 allele was successfully genotyped in 75% (213/285) of the study participants. The CYP2C8*2A allele had a frequency of 63%, whereas the CYP2C8*2T allele had a frequency of 37%. Genotypes CYP2C8*2AA (rapid metabolizer), CYP2C8*2AT (intermediate metabolizer), and CYP2C8*2TT (poor metabolizer) were observed in 44%, 38%, and 18% of the investigated participants, respectively. Conclusions: This study gives the first description of CYP2C8*2 allele distribution in the Republic of Congo and highlights the potential risk of amodiaquine-related adverse events. Information from this study will be beneficial during pharmacovigilance investigations.

Influence of Cytochrome P450 (CYP) 2C8 Polymorphisms on the Efficacy and Tolerability of Artesunate-Amodiaquine Treatment of Uncomplicated Plasmodium Falciparum Malaria in Zanzibar

“…The observed CYP2C8*3 (2.7%) allele frequency was consistent with our previous study [17], suggesting that Zanzibar is a region in Africa with relatively high CYP2C8*3 prevalence, as compared with other African regions [3,16,19]. The CYP2C8*2 allele frequency (17.5%) is more in line with most previous reports from the African continent [3, 18-20, 29, 30], but not as high as was recently reported in the Brazzaville, Republic of Congo (37%) [21]. Our results show that CYP2C8*2 and CYP2C8*3 carriers were at increased risk of presenting with adverse events after ASAQ treatment, but without increased risk of experiencing newly acquired or recrudescent P. falciparum infections during a 42-day follow-up.…”

“…This reduction was however, not associated with treatment outcome or occurrence of adverse events, although the small sample size (N = 81) was lifted as a limiting factor in these analyses. Finally, despite no direct assessments of the association between CYP2C8*2 genotypes and occurrence of adverse events in Congo, the high CYP2C8*2 allele frequency (37%) reported in Brazzaville has been suggested to have had implications on the choice of rst line treatment in the country [21]. ASAQ and AL were the rst-and second-line treatments respectively, when ACTs where rst introduced into the national treatment guidelines in 2006.…”

“…However, the prolonged pharmacokinetic pro le in poor-metabolizers may lead to a non-negligible increased risk of amodiaquine-related adverse events among populations with these speci c genotypes [14,19,20]. Albeit of interest, only a few studies have investigated the potential association between slow amodiaquine metabolizers and reduced treatment e cacy and/or increased risk of adverse events [3,[20][21][22]. In vivo data on the impact of the low activity CYP2C8*2 allele are sparse, and almost non-existent among CYP2C8*3 carriers due to the very low CYP2C8*3 allele frequency in the generality of African populations, where ASAQ is primary used [6,14].…”

Influence of cytochrome P450 (CYP) 2C8 polymorphisms on the efficacy and tolerability of artesunate‐amodiaquine treatment of uncomplicated Plasmodium falciparum malaria in Zanzibar

“…The observed CYP2C8*3 allele frequency (2.7 %) was consistent with previous reports [18], suggesting that Zanzibar is a region in Africa with relatively high CYP2C8*3 prevalence, compared with other African regions [16,17,20]. The CYP2C8*2 allele frequency (17.5 %) is in line with most previous reports from the African continent [16, 19-21, 30, 31], but not as high as was recently reported in Brazzaville, Republic of Congo (37 %) [22]. The present study results show that CYP2C8*2 and CYP2C8*3 carriers were at increased risk of presenting with adverse events after AS-AQ treatment, but without increased risk of experiencing newly acquired or recrudescent P. falciparum infections during a 42-day follow-up.…”

“…However, the prolonged pharmacokinetic profile in poor metabolizers may lead to a non-negligible increased risk of AQ-related adverse events among populations with these specific genotypes [14,20,21]. Albeit of interest, only a few studies have investigated the potential association between slow AQ metabolizers and reduced treatment efficacy and/or increased risk of adverse events [16,[21][22][23]. In vivo data on the impact of the low activity CYP2C8*2 allele are sparse, and almost non-existent among CYP2C8*3 carriers due to the very low CYP2C8*3 allele frequency in the generality of African populations, where AS-AQ is primarily used [6,14].…”