Effect of Concomitant Artesunate Administration and Cytochrome P4502C8 Polymorphisms on the Pharmacokinetics of Amodiaquine in Ghanaian Children with Uncomplicated Malaria

Abstract

Artesunate (AS) is used in combination with amodiaquine (AQ) as first-line treatment for uncomplicated malaria in many countries. We investigated the effect of concomitant AS administration on the pharmacokinetics of AQ and compared concentrations of desethylamodiaquine (DEAQ), the main metabolite of AQ, in plasma between patients with different variants of the cytochrome P4502C8 (CYP2C8) gene. A two-compartment model was fitted to 169 plasma DEAQ concentrations from 103 Ghanaian children aged 1 to 14 years with uncomplicated malaria treated either with AQ alone (n ‫؍‬ 15) or with AS plus AQ (n ‫؍‬ 88). The population clearance of DEAQ appeared to increase nonlinearly with body weight, and the central volume of distribution of DEAQ was higher (P < 0.001) in the AS-plus-AQ group than in the AQ-only group. The maximum plasma DEAQ concentration was higher (P < 0.001), and the population distribution half-life was shorter (P < 0.01), in the AQ-only group than in the AS-plus-AQ group. The total areas under the plasma DEAQ concentrationtime curves (P ‫؍‬ 0.68) and elimination half-lives (P ‫؍‬ 0.39) were similar for the two groups. There was a high frequency (0.179) of the non-wild-type allele of CYP2C8, but no differences between CYP2C8 genotypes with regard to AQ efficacy or safety were evident. The sample size, however, was limited, so monitoring of AQ toxicity in the study area is still indicated. The nonlinear clearance of DEAQ and the wide variability in kinetic parameters have safety implications for weight-based dosing of higher-body-weight children with AQ. The pharmacokinetics of artemisinin combination therapies should be studied in malaria patients, because the rapid parasite clearance caused by the artemisinin may affect the kinetics of the partner drug and the combination.Prompt treatment with safe and efficacious antimalarial drugs is an important malaria control strategy. This strategy is being challenged by the escalating resistance of Plasmodium falciparum to the available drugs (33). Artemisinin combination therapy (ACT) is recommended as a rational approach to curb this problem of escalating antimalarial drug resistance (31). Many countries in sub-Saharan Africa have adopted ACT as their first-line malaria treatment policy. The combination of artesunate (AS) with amodiaquine (AQ) is one of the most widely adopted ACT regimens.AQ is a 4-aminoquinoline that is rapidly absorbed and extensively metabolized upon oral administration to desethylamodiaquine (DEAQ), its main and active metabolite (7,8). The formation of DEAQ from AQ is catalyzed by cytochrome P4502C8 (CYP2C8), a polymorphic isoform of hepatic cytochrome P450 (18). The gene for CYP2C8 is located in a cluster with the genes for CYP2C9, CYP2C19, and CYP2C18 on chromosome 10q24 (11). CYP2C8*2 and CYP2C8*3 are the two most frequently occurring variant alleles of CYP2C8, and both variants code for enzymes with decreased activity (9, 10, 23), raising the possibility that polymorphisms in the CYP2C8 gene may modulate the metabolism of AQ (5).AS is ...

Population Pharmacokinetic and Pharmacodynamic Modeling of Amodiaquine and Desethylamodiaquine in Women with Plasmodium vivax Malaria during and after Pregnancy

“…Three previous studies have described the pharmacokinetic properties of amodiaquine and desethylamodiaquine in nonpregnant adults and children using nonlinear mixed-effects modeling (2,17,23). A nonlinear mixed-effects approach, in contrast to results from a noncompartmental analysis, provides a mechanistic understanding of the pharmacokinetic properties of the drug with the ability to characterize potential covariate relationships with higher statistical power.…”

“…Interindividual random variability in all parameters was modeled exponentially: i ϭ ϫ exp( i, ), where i is the individually estimated parameter value for the ith patient, is the typical parameter value for the modeled population, and i, is the interindividual random variability assumed to be normally distributed with a zero mean and variance 2 . Correlations between variability components were evaluated.…”

“…The pharmacokinetic properties of amodiaquine and desethylamodiaquine have been investigated in healthy volunteers, patients with P. falciparum malaria, and children (2,17,20,23,37,38,40,45,52,53,60,64,65). A multiphasic exponential decline has been suggested for both amodiaquine and desethylamodiaquine, with terminal elimination half-lives of approximately 10 h and 10 days, respectively (25).…”

Priority pharmacogenetics for the African continent: focus on CYP450

“…Furthermore, in eastern Africa, where malaria is ranked second in terms of its contribution to DALYs, only two countries have been investigated. In western Africa, where malaria is the highest contributor to disease burden, three countries have allelic frequency data for CYP2C8, namely Burkina Faso [34,35], Ghana [36][37][38] and…”

Can pharmacogenomics improve malaria drug policy?

“…Studies in Burkina Faso and Ghana have not revealed a relationship between drug efficacy and CYP2C8 genotype. 30,31 While the percentage of the population with an inactivating CYP2C8 genetic variant is not high in most malaria-endemic regions, the overall incidence of risk is significant due to the burden of disease. For example, Cavaco et al estimated that the CYP2C8*2 and CYP2C8*3 genetic variants occur in 2.1% of the population in Zanzibar, United Republic of Tanzania: this translates into more than 30 000 patients per year at risk for severe drug reactions to amodiaquine (of a malaria patient population of ~1 000 000).…”