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

British journal of clinical pharmacology (2014-10-10)
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

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. 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. 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. 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
2′,3′-Dideoxyinosine, ≥98% (HPLC)
Supelco
HybridSPE®-Phospholipid, 96-well Plate, bed wt. 50 mg, volume 2 mL, pk of 1
Ritonavir, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Ritonavir, ≥98% (HPLC)
Didanosine, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Artemether, ≥98% (HPLC)
Sigma-Aldrich
3′-Azido-3′-deoxythymidine, ≥98% (HPLC)
Sigma-Aldrich
Lumefantrine
USP
Zidovudine, United States Pharmacopeia (USP) Reference Standard
Supelco
Zidovudine, Pharmaceutical Secondary Standard; Certified Reference Material
Didanosine for system suitability, European Pharmacopoeia (EP) Reference Standard
Zidovudine, European Pharmacopoeia (EP) Reference Standard