Clinical pharmacokinetic drug interactions associated with artemisinin derivatives and HIV-antivirals

Abstract

Management of HIV and malaria co-infection is challenging due to potential drug-drug interactions between antimalarial and HIV-antiviral drugs. Little is known of the clinical significance of these drug interactions, and this review provides a comprehensive summary and critical evaluation of the literature. Specifically, drug interactions between WHO-recommended artemisinin combination therapies (ACT) and HIV-antivirals are discussed. An extensive literature search produced eight articles detailing n = 44 individual pharmacokinetic interactions. Only data pertaining to artemether-lumefantrine and two other artesunate combinations are available, but most of the interactions are characterized on at least two occasions by two different groups. Overall, protease inhibitors (PIs) tended to increase the exposure of lumefantrine and decrease the exposures of artemether and dihydroartemisinin, a pharmacologically active metabolite of artemether. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) tended to decrease the exposures of artemether, dihydroartemisinin, and lumefantrine when co-administered with artemether-lumefantrine. Fewer studies characterized the effects of PIs or NNRTIs on artesunate combinations, but nevirapine increased artesunate exposure and ritonavir decreased dihydroartemisinin exposure. On the other hand, artemether-lumefantrine or artesunate combinations had little effect on the pharmacokinetics of HIV-antivirals, with the exception of decreased nevirapine exposure from artemether-lumefantrine or increased ritonavir exposure from pyronaridine/artesunate co-administration. In general, pharmacokinetic interactions can be explained by the metabolic properties of the co-administered drugs. Despite several limitations to the studies, these data do provide valuable insights into the potential pharmacokinetic perturbations, and the consistently marked elevation or reduction in ACT exposure in some cases cannot be overlooked.