Concomitant efavirenz reduces pharmacokinetic exposure to the antimalarial drug artemether-lumefantrine in healthy volunteers

Abstract

Background: The antiretroviral drug efavirenz (EFV) and the antimalarial artemisinin-based combination therapy artemether-lumefantrine (AL) are commonly co-administered to treat HIV and malaria. EFV is a known inducer of cytochrome P450 3A4, which converts artemether to dihydroartemisinin (DHA) that is also active and metabolizes longer acting lumefantrine (LR). A study in healthy volunteers was completed to address the concern that EFV impacts AL pharmacokinetics (PKs).

Methods: Adults received AL (80/480 mg twice daily) for 3-days before and during EFV co-administration (600 mg daily for 26 days) with intensive PK for artemether, DHA, and LR conducted after the last AL dose for each period. EFV PK was evaluated with and without AL. PK parameters were estimated using noncompartmental methods.

Results: Twelve subjects completed the 2-period study. PK exposure for artemether, DHA, and LR [as estimated by the area under the concentration time curve (AUClast)] decreased or trended toward decrease with EFV, compared with when administered alone [-51% (P = 0.084), -46% (P = 0.005), and -21% (P = 0.102), respectively]. Day-7 LR levels, previously deemed predictive of treatment success, were 46% lower (P = 0.002) with EFV, but the LR half-life was unchanged. EFV PK exposure was minimally altered after AL co-administration [AUC0-24 hrs decreased by 17% (P = 0.034)].

Conclusions: Exposure to DHA, but not LR, was significantly lower during EFV-AL co-administration compared with that during administration of AL alone. These findings may have implications for the treatment efficacy of AL, particularly in children. However, the observed modest changes probably do not warrant dosage adjustment during co-administration of AL with EFV.

Fig. 1

Study scheme. AL, artemether/lumefantrine; EFV, efavirenz; BID, twice daily.

Fig. 2

Mean plasma concentration versus time profile for artemether, dihydroartemisinin, and lumefantrine after AL administration alone (solid line) and with EFV (dash line). The insert is a blow-up figure for ARM (circle) /DHA (triangle). Error bar represented standard deviation (SD). Ideal PK time was used as X-axis,

Fig. 3

Mean plasma concentration versus time profile for efavirenz after EFV administration alone (solid line) and with AL (dash line). Error bar represented standard deviation (SD).