Effect of Pregnancy on the Pharmacokinetic Interaction between Efavirenz and Lumefantrine in HIV-Malaria Coinfection

Abstract

Artemether-lumefantrine is often coadministered 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 nonpregnant adults. The influence of pregnancy on this interaction has not been reported. This pharmacokinetic study involved 35 pregnant and 34 nonpregnant HIV-malaria-coinfected women receiving efavirenz-based antiretroviral therapy and was conducted in four health facilities in Nigeria. Participants received a 3-day standard regimen of artemether-lumefantrine for malaria treatment, and intensive pharmacokinetic sampling was conducted from 0.5 to 96 h after the last dose. Plasma efavirenz, lumefantrine, and desbutyl-lumefantrine were quantified using validated assays, and pharmacokinetic parameters were derived using noncompartmental analysis. The median middose plasma concentrations of efavirenz were significantly lower in pregnant women ( = 32) than in nonpregnant women ( = 32) at 1,820 ng/ml (interquartile range, 1,300 to 2,610 ng/ml) versus 2,760 ng/ml (interquartile range, 2,020 to 5,640 ng/ml), respectively ( = 0.006). The lumefantrine area under the concentration-time curve from 0 to 96 h was significantly higher in pregnant women ( = 27) at 155,832 ng · h/ml (interquartile range, 102,400 to 214,011 ng · h/ml) than nonpregnant women at 90,594 ng · h/ml (interquartile range, 58,869 to 149,775 ng · h/ml) ( = 0.03). A similar trend was observed for the lumefantrine concentration at 12 h after the last dose of lumefantrine, which was 2,870 ng/ml (interquartile range, 2,180 to 4,880 ng/ml) versus 2,080 ng/ml (interquartile range, 1,190 to 2,970 ng/ml) in pregnant and nonpregnant women, respectively ( = 0.02). The lumefantrine-to-desbutyl-lumefantrine ratio also tended to be lower in pregnant women than in nonpregnant women ( = 0.076). 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 endpoints.

Anti‐Infective Dosing in Special Populations: Pregnancy

“…Six studies published following this meta‐analysis were identified 15–20 . Out of these, five were inconclusive regarding need for dose adjustments but rather commented that the clinical relevance of statistically significant differences in pharmacokinetic parameters warrants further evaluation.…”

“…Six studies published following this meta-analysis were identified. [15][16][17][18][19][20] Out of these, five were inconclusive regarding need for dose adjustments but rather commented that the clinical relevance of statistically significant differences in pharmacokinetic parameters warrants further evaluation. All the studies used day-7 lumefantrine concentrations of either >175 ng/mL or >280 ng/mL as a proxy for adequate dosing to avoid treatment failure, based on the demonstrated correlation between concentrations below these targets and risk of recrudescent malaria.…”

Drug–Drug Interactions with Antiretroviral Drugs in Pregnant Women Living with HIV: Are They Different from Non-Pregnant Individuals?

“…Adegbola et al examined the DDI between the antiretroviral EFV and the antimalarial LF in pregnant women compared to women postpartum [72]. Lumefantrine is primarily metabolized by CYP3A4 and EFV induces CYP3A4 activity, resulting in a decreased LF exposure in non-pregnant patients as showed in Fig.…”

“…Lumefantrine is primarily metabolized by CYP3A4 and EFV induces CYP3A4 activity, resulting in a decreased LF exposure in non-pregnant patients as showed in Fig. 2a [72,73]. Pregnant women treated with LF have ~ 30% lower LF concentrations at day 7, a marker for therapeutic efficacy, compared with nonpregnant women [74][75][76][77].…”

Efavirenz-Based Antiretroviral Therapy Reduces Artemether–Lumefantrine Exposure for Malaria Treatment in HIV-Infected Pregnant Women

“…[22][23][24][25][26][27] Despite the wide-spread use of AL, no reports to our knowledge have addressed the effects of efavirenz-based ART on AL pharmacokinetics in HIV-infected pregnant women; previous studies have only investigated the effects of pregnancy on this treatment combination. 28 Our goal is to inform specific artemether-lumefantrine dosing guidelines for efavirenz-treated HIV-infected pregnant women.…”