An Individual Participant Data Population Pharmacokinetic Meta-analysis of Drug-Drug Interactions between Lumefantrine and Commonly Used Antiretroviral Treatment

Abstract

Treating malaria in HIV-coinfected 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 10 studies with 6,100 lumefantrine concentrations from 793 nonpregnant adult participants (41% HIV-malaria-coinfected, 36% malaria-infected, 20% HIV-infected, and 3% healthy volunteers). Lumefantrine exposure increased 3.4-fold with coadministration of lopinavir-ritonavir-based antiretroviral therapy (ART), while it decreased by 47% with efavirenz-based ART and by 59% in the patients with rifampin-based antituberculosis 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 rifampin 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 subtherapeutic 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 rifampin, respectively.

Keywords: drug-drug interactions; human immunodeficiency virus; lumefantrine; population pharmacokinetics; uncomplicated malaria.

FIG 1

Visual predictive check of lumefantrine concentrations versus time, stratified by study and treatment arm. CTRL, control arm; Ph, phase. The observed lumefantrine concentrations (in the log scale) versus time after the first dose are displayed as blue dots. The solid and dashed lines are the 50th, 5th, and 95th percentiles of the observed plasma concentration, while the shaded areas are the 90% confidence intervals for the same percentiles, as predicted by the model. The three panels correspond to the data collected from 0 to 24 h, 25 to 220 h, and 221 to 1,175 h after the first dose, respectively.

FIG 1

Visual predictive check of lumefantrine concentrations versus time, stratified by study and treatment arm. CTRL, control arm; Ph, phase. The observed lumefantrine concentrations (in the log scale) versus time after the first dose are displayed as blue dots. The solid and dashed lines are the 50th, 5th, and 95th percentiles of the observed plasma concentration, while the shaded areas are the 90% confidence intervals for the same percentiles, as predicted by the model. The three panels correspond to the data collected from 0 to 24 h, 25 to 220 h, and 221 to 1,175 h after the first dose, respectively.

FIG 1

Visual predictive check of lumefantrine concentrations versus time, stratified by study and treatment arm. CTRL, control arm; Ph, phase. The observed lumefantrine concentrations (in the log scale) versus time after the first dose are displayed as blue dots. The solid and dashed lines are the 50th, 5th, and 95th percentiles of the observed plasma concentration, while the shaded areas are the 90% confidence intervals for the same percentiles, as predicted by the model. The three panels correspond to the data collected from 0 to 24 h, 25 to 220 h, and 221 to 1,175 h after the first dose, respectively.

FIG 2

Simulated day 7 concentration of lumefantrine with various drug-drug interactions in the analysis. The box represents the 25th to 75th percentiles, and the whiskers represent the 2.5th to 97.5th percentiles of the simulated day 7 concentration after Monte Carlo simulations (n = 10,000). The dashed line at 200 ng/ml denotes the suggested threshold.