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

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


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: NCT00619944 NCT00620438.

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

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anti-HIV Agents* / administration & dosage
  • Anti-HIV Agents* / pharmacokinetics
  • Anti-HIV Agents* / therapeutic use
  • Antimalarials* / administration & dosage
  • Antimalarials* / pharmacokinetics
  • Artemether
  • Artemisinins* / administration & dosage
  • Artemisinins* / pharmacokinetics
  • Biological Availability
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Ethanolamines* / administration & dosage
  • Ethanolamines* / pharmacokinetics
  • Female
  • Fluorenes* / administration & dosage
  • Fluorenes* / pharmacokinetics
  • Humans
  • Lumefantrine
  • Male
  • Middle Aged
  • Models, Biological*
  • Young Adult


  • Anti-HIV Agents
  • Antimalarials
  • Artemisinins
  • Ethanolamines
  • Fluorenes
  • Artemether
  • Lumefantrine

Associated data