CYP2B6*6 Genotype Specific Differences in Artemether‐Lumefantrine Disposition in Healthy Volunteers

Abstract

Cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of the antimalarial drugs artemether and lumefantrine. Here we investigated the effect of CYP2B6*6 on the plasma pharmacokinetics of artemether, lumefantrine, and their metabolites in healthy volunteers. Thirty healthy and previously genotyped adult volunteers—15 noncarriers (CYP2B6*1/*1) and 15 homozygote carriers (CYP2B6*6/*6)—selected from a cohort of 150 subjects from the Ilorin metropolitan area were administered the complete 3‐day course of artemether and lumefantrine (80 and 480 mg twice daily, respectively). Intensive pharmacokinetic sampling was conducted at different time points before and after the last dose. Plasma concentrations of artemether, lumefantrine, dihydroartemisinin, and desbutyllumefantrine were quantified using validated liquid chromatography–mass spectrometric methods. Pharmacokinetic parameters were evaluated using noncompartmental analysis. Artemether clearance of CYP2B6*6/*6 volunteers was nonsignificantly lower by 26% (ratios of geometric mean [90% CI]; 0.74 [0.52‐1.05]), and total exposure (the area under the plasma concentration‐time curve from time 0 to infinity [AUC0‐∞]) was greater by 35% (1.35 [0.95‐1.93]) when compared with those of *1/*1 volunteers. Similarly, assuming complete bioconversion from artemether, the dihydroartemisinin AUC0‐∞ was 22% lower. On the contrary, artemether‐to‐dihydroartemisinin AUC0‐∞ ratio was 73% significantly higher (1.73 [1.27‐2.37]). Comparison of lumefantrine exposure and lumefantrine‐to‐desbutyllumefantrine metabolic ratio of *6/*6 with corresponding data from *1/*1 volunteers showed no differences. The increased artemether‐to‐dihydroartemisinin metabolic ratio of *6/*6 volunteers is unlikely to result in differences in artemether‐lumefantrine efficacy and treatment outcomes. This is the first study in humans to associate CYP2B6*6 genotype with artemether disposition.

Therapeutic efficacy of generic artemether–lumefantrine in the treatment of uncomplicated malaria in Ghana: assessing anti-malarial efficacy amidst pharmacogenetic variations

“…The effect on metabolic ratio is that these genotypes *6/*6 + *18/*18 have higher metabolic ratios than *1/*1 carriers. The observation in our study is similar to a study which found a significant increase in the metabolic ratio of artemether-to-dihydroartemisinin of CYP2B6*6/*6 volunteers over their *1/*1 counterparts [ 40 ]. There is less pharmacokinetic data on dihydroartemisinin (DHA), which is considered a very potent metabolite of artemether, and in this study, we quantified plasma DHA and observed a median concentration range of 11.45–90.90 ng/mL.…”

“…Major findings from the study are that CYP3A5 genotypes influences plasma AL metabolism and thus plasma concentrations whereas CYP3A5 *3 and *6 is associated with elevated levels of AL and metabolites. While several studies have explored effect of pharmacogenetics on AL [ 20 , 36 , 40 ] treatment in different populations, this study is unique in its evaluation of cytochrome P450 variation on plasma metabolite concentrations of generic AL and its effects on parasitaemia in Ghanaians. Understanding the role of pharmacogenetics in drug metabolism is crucial, especially in discerning how variations in key drug-metabolizing enzymes involved in AL metabolism might influence drug disposition and parasite clearance.…”

Differential Impact of Nevirapine on Artemether-Lumefantrine Pharmacokinetics in Individuals Stratified by CYP2B6 c.516G>T Genotypes

“…Rather, effect sizes and the associated confidence intervals and P values are presented to permit individual interpretation of relative weight of the results and conclusion. Comparison of genotype effect on artemether-lumefantrine pharmacokinetics in the absence of nevirapine has been described elsewhere (47). Furthermore, the relatively small sample sizes (particularly in the GG subgroups) may have reduced the power to detect differences in some of the pharmacokinetic parameters.…”

Drug‐Drug Interactions of Artemisinin‐Based Combination Therapies in Malaria Treatment: A Narrative Review of the Literature

“…From another small clinical study, it appears likely that the CYP2B6*6 genotype is responsible for poor metabolizer status in individuals given artemether. 10 The artemether clearance was lowered by 22% with a 35% increase in area under the plasma concentrationtime curve (AUC) from time 0 to infinity. This was in part attributed to decreased metabolism to dihydroartemisinin by 22% and significantly increased the artemether-to-dihydroartemisinin AUC from time 0 to infinity ratio by 73%.…”

“…Poor metabolizing of CYP2B6 can therefore result in lower levels of dihydroartemisinin concentrations, although this was not observed in a clinically significant manner in the SNP study. From another small clinical study, it appears likely that the CYP2B6*6 genotype is responsible for poor metabolizer status in individuals given artemether 10 . The artemether clearance was lowered by 22% with a 35% increase in area under the plasma concentration–time curve (AUC) from time 0 to infinity.…”