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Br J Clin Pharmacol. 2015 Apr;79(4):636-49. doi: 10.1111/bcp.12529.

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

Author information

1
Unit for Pharmacokinetics and Drug Metabolism, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.

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

PMID:
25297720
PMCID:
PMC4386948
DOI:
10.1111/bcp.12529
[Indexed for MEDLINE]
Free PMC Article

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