Artemether-lumefantrine co-administration with antiretrovirals: population pharmacokinetics and dosing implications

Richard M Hoglund, Pauline Byakika-Kibwika, Mohammed Lamorde, Concepta Merry, Michael Ashton, Warunee Hanpithakpong, Nicholas P J Day, Nicholas J White, Angela Äbelö, Joel Tarning, Richard M Hoglund, Pauline Byakika-Kibwika, Mohammed Lamorde, Concepta Merry, Michael Ashton, Warunee Hanpithakpong, Nicholas P J Day, Nicholas J White, Angela Äbelö, Joel Tarning

Abstract

Aim: Drug-drug interactions between antimalarial and antiretroviral drugs may influence antimalarial treatment outcomes. The aim of this study was to investigate the potential drug-drug interactions between the antimalarial drugs, lumefantrine, artemether and their respective metabolites desbutyl-lumefantrine and dihydroartemisinin, and the HIV drugs efavirenz, nevirapine and lopinavir/ritonavir.

Method: Data from two clinical studies, investigating the influence of the HIV drugs efavirenz, nevirapine and lopinavir/ritonavir on the pharmacokinetics of the antimalarial drugs lumefantrine, artemether and their respective metabolites, in HIV infected patients were pooled and analyzed using a non-linear mixed effects modelling approach.

Results: Efavirenz and nevirapine significantly decreased the terminal exposure to lumefantrine (decrease of 69.9% and 25.2%, respectively) while lopinavir/ritonavir substantially increased the exposure (increase of 439%). All antiretroviral drugs decreased the total exposure to dihydroartemisinin (decrease of 71.7%, 41.3% and 59.7% for efavirenz, nevirapine and ritonavir/lopinavir, respectively). Simulations suggest that a substantially increased artemether-lumefantrine dose is required to achieve equivalent exposures when co-administered with efavirenz (250% increase) and nevirapine (75% increase). When co-administered with lopinavir/ritonavir it is unclear if the increased lumefantrine exposure compensates adequately for the reduced dihydroartemisinin exposure and thus whether dose adjustment is required.

Conclusion: There are substantial drug interactions between artemether-lumefantrine and efavirenz, nevirapine and ritonavir/lopinavir. Given the readily saturable absorption of lumefantrine, the dose adjustments predicted to be necessary will need to be evaluated prospectively in malaria-HIV co-infected patients.

Trial registration: ClinicalTrials.gov NCT00619944 NCT00620438.

Keywords: artemether-lumefantrine; drug-drug interaction; efavirenz; lopinavir/ritonavir; nevirapine; population pharmacokinetics.

© 2014 The Authors. British Journal of Clinical Pharmacology published by. John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

Figures

Figure 1
Figure 1
Basic goodness-of-fit plots for the final lumefantrine/desbutyl-lumefantrine model. Observations plotted against individual predicted concentrations of lumefantrine (A) and desbutyl-lumefantrine (C). Conditional weighted residuals of lumefantrine (B) and desbutyl-lumefantrine (D) plotted against time after dose. The solid line is the identity line and the broken line is the locally weighted least square regression line. The concentrations are presented on a logarithmic (base 10) axis
Figure 2
Figure 2
Visual predictive checks of the final models for lumefantrine (A), desbutyl-lumefantrine (B), artemether (C), and dihydroartemisinin (D), based on 2000 simulations. Open circles represent the observations and solid lines represent the 5th, 50th and 95th percentiles of the observed data. The shaded areas represent the 95% confidence intervals around the simulated 5th, 50th and 95th percentiles. The concentrations are presented on a logarithmic (base 10) axis
Figure 3
Figure 3
Basic goodness-of-fit plots for the artemether/dihydroartemisinin model. Observations plotted against individual predicted concentrations of artemether (A) and dihydroartemisinin (C). Conditional weighted residuals of artemether (B) and dihydroartemisinin (D) plotted against time after dose. The solid line is the identity line and the broken line is the locally weighted least square regression line. The concentrations are presented on a logarithmic (base 10) axis
Figure 4
Figure 4
Box (25th to 75th percentile) and whisker (1.5 × interquartile range) plot of dose simulations. The top row illustrates the simulated terminal exposures (AUC) from 72 to 894 h for lumefantrine when given alone, in combination with HIV treatment and after an adjusted dose regimen [efavirenz (A), nevirapine (B) and lopinavir/ritonavir (C)]. The middle row illustrates the simulated exposures (AUC) from 0 to 894 h for dihydroartemisinin when given alone, in combination with HIV treatment and after an adjusted dose regimen [efavirenz (D), nevirapine (E) or lopinavir/ritonavir (F)]. The bottom row illustrates the simulated day 7 concentrations for lumefantrine when given alone, in combination with HIV treatment and after an adjusted dose regimen [efavirenz (G), nevirapine (H) or lopinavir/ritonavir (I)]. The dotted lines in the top and middle rows represent the standard exposures when the antimalarial treatment is given alone. The dotted lines in the bottom row represent previously defined day 7 cut-off concentration for therapeutic failure of 280 ng ml−1 and 175 ng ml−1

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