Evidence of Microbiome-Drug Interactions between the Antimalarial Lumefantrine and Gut Microbiota in Mice.

The antimalarial drug lumefantrine (LF) exhibits erratic pharmacokinetics (PK). Intersubject variability might be attributed, in part, to differences in the gut microbiome-mediated drug metabolism. We assessed LF disposition in healthy mice stratified by enterotype to explore associations between the gut microbiota and LF PK. Gut microbiota enterotypes were classified according to abundance and diversity indices from 16S rRNA sequencing. Pharmacokinetic parameters were computed using noncompartmental analysis. Two distinctive enterotypes were identified. Maximal concentration (Cmax) and total drug exposure measured as the area under the drug concentration-time curve (AUC0-24) differed significantly between the groups. The mean and SD of Cmax were 660 ± 220 ng/mL versus 390 ± 59 ng/mL (P = 0.02), and AUC0-24 was 9,600 ± 2,800 versus 5,800 ± 810 ng × h/mL (P = 0.01). In healthy mice intragastrically dosed with the antimalarial drug LF in combination with artemether, LF exposure was associated with the gut bacterial community structure. Studies of xenobiotic-microbiota interactions can inform drug posology and elucidate mechanisms of drug disposition.