An Individual Participant Data Population Pharmacokinetic Meta-Analysis of Drug-drug Interactions between Lumefantrine and Commonly-used Antiretroviral Treatment

Treating malaria in HIV co-infected individuals should consider potential drug-drug interactions. Artemether-lumefantrine is the most widely recommended treatment for uncomplicated malaria globally. Lumefantrine is metabolized by CYP3A4, an enzyme that commonly-used antiretrovirals often induce or inhibit. A population pharmacokinetic meta-analysis was conducted using individual participant data from ten studies, with 6,100 lumefantrine concentrations from 793 non-pregnant adult participants (41% HIV-malaria co-infected, 36% malaria-infected, 20% HIV-infected, and 3% healthy volunteers). Lumefantrine exposure increased 3.4-fold with co-administration of lopinavir/ritonavir-based antiretroviral therapy (ART), while it decreased by 47% with efavirenz-based ART and by 59% in the patients with rifampicin-based anti-tuberculosis treatment. Nevirapine- or dolutegravir-based ART and malaria- or HIV-infection were not associated with significant effects. Monte Carlo simulations showed that those on concomitant efavirenz or rifampicin have 49% and 80% probability of day-7 concentrations <200 ng/mL respectively, a threshold associated with an increased risk of treatment failure. The risk of achieving sub-therapeutic concentrations increases with larger body weight. An extended 5-day and 6-day artemether-lumefantrine regimen is predicted to overcome these drug-drug interactions with efavirenz and rifampicin respectively.