Effect of pregnancy on the pharmacokinetic interaction between efavirenz and lumefantrine in HIV-malaria co-infection [PublishAheadOfPrint]

Background: Artemether-lumefantrine is often co-administered with efavirenz-based antiretroviral therapy for malaria treatment in HIV-infected women during pregnancy. Previous studies showed changes in lumefantrine pharmacokinetics due to interaction with efavirenz in non-pregnant adults. The influence of pregnancy on this interaction has not been reported.

Method: This pharmacokinetic study involved 35 pregnant and 34 non-pregnant HIV-malaria co-infected women receiving efavirenz-based antiretroviral therapy and was conducted in four health facilities in Nigeria. Participants received three-day standard regimen of artemether-lumefantrine for malaria treatment and intensive pharmacokinetic sampling was conducted 0.5-96 hours after the last dose. Plasma efavirenz, lumefantrine and desbutyl-lumefantrine were quantified using validated assays and pharmacokinetic parameters were derived using noncompartmental analysis.

Results: Median (interquartile range) mid-dose plasma concentrations of efavirenz was significantly lower in pregnant (n = 32) compared with non-pregnant (n = 32) women at 1820 (1300-2610) ng/mL vs 2760 (2020-5640) ng/mL, p = 0.006. Lumefantrine AUC_0-96 was significantly higher in pregnant women (n = 27) at 155,832 (102,400-214,011) ng/mL*h compared with non-pregnant women at 90,594 (58,869-149,775) ng/mL*h, p = 0.03. A similar trend was observed for lumefantrine C₁₂, 2870 (2180-4880) vs 2080 (1190-2970) ng/mL, respectively (p = 0.02). Lumefantrine to desbutyl-lumefantrine ratio also tended to be lower in pregnant than non-pregnant women (P = 0.076).

Conclusion: Overall, pregnancy tempered the extent of efavirenz-lumefantrine interactions resulting in increased lumefantrine exposure. However, any consideration of dosage adjustment for artemether-lumefantrine to enhance exposure in this population needs to be based on data from a prospective study with safety and efficacy end points.

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