Significant pharmacokinetic interactions between artemether/lumefantrine and efavirenz or nevirapine in HIV-infected Ugandan adults

Co-administration of artemether/lumefantrine with antiretroviral therapy has potential for pharmacokinetic drug interactions. We investigated drugdrug interactions between artemether/lumefantrine and efavirenz or nevirapine. We performed a cross-over study in which HIV-infected adults received standard six-dose artemether/lumefantrine 80/480 mg before and at efavirenz or nevirapine steady state. Artemether, dihydroartemisinin, lumefantrine, efavirenz and nevirapine plasma concentrations were measured and compared. Efavirenz significantly reduced artemether maximum concentration (C-max) and plasma AUC (median 29 versus 12 ng/mL, P0.01, and 119 versus 25 ngh/mL, P0.01), dihydroartemisinin C-max and AUC (median 120 versus 26 ng/mL, P0.01, and 341 versus 84 ngh/mL, P0.01), and lumefantrine C-max and AUC (median 8737 versus 6331 ng/mL, P0.03, and 280370 versus 124381 ngh/mL, P0.01). Nevirapine significantly reduced artemether C-max and AUC (median 28 versus 11 ng/mL, P0.01, and 123 versus 34 ngh/mL, P0.01) and dihydroartemisinin C-max and AUC (median 107 versus 59 ng/mL, P0.01, and 364 versus 228 ngh/mL, P0.01). Lumefantrine C-max and AUC were non-significantly reduced by nevirapine. Artemether/lumefantrine reduced nevirapine C-max and AUC (median 8620 versus 4958 ng/mL, P0.01, and 66329 versus 35728 ngh/mL, P0.01), but did not affect efavirenz exposure. Co-administration of artemether/lumefantrine with efavirenz or nevirapine resulted in a reduction in artemether, dihydroartemisinin, lumefantrine and nevirapine exposure. These drug interactions may increase the risk of malaria treatment failure and development of resistance to artemether/lumefantrine and nevirapine. Clinical data from population pharmacokinetic and pharmacodynamic trials evaluating the impact of these drug interactions are urgently needed.