Interaction between Artemether-Lumefantrine and Nevirapine-Based Antiretroviral Therapy in HIV-1-Infected Patients

Abstract

Artemether-lumefantrine and nevirapine-based antiretroviral therapy (ART) are the most commonly recommended first-line treatments for malaria and HIV, respectively, in Africa. Artemether, lumefantrine, and nevirapine are metabolized by the cytochrome P450 3A4 enzyme system, which nevirapine induces, creating potential for important drug interactions. In a parallel-design pharmacokinetic study, concentration-time profiles were obtained in two groups of HIV-infected patients: ART-naïve patients and those stable on nevirapine-based therapy. Both groups received the recommended artemether-lumefantrine dose. Patients were admitted for intense pharmacokinetic sampling (0 to 72 h) with outpatient sampling until 21 days. Concentrations of lumefantrine, artemether, dihydroartemisinin, and nevirapine were determined by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. The primary outcome was observed day 7 lumefantrine concentrations, as these are associated with therapeutic response in malaria. We enrolled 36 patients (32 females). Median (range) day 7 lumefantrine concentrations were 622 ng/ml (185 to 2,040 ng/ml) and 336 ng/ml (29 to 934 ng/ml) in the nevirapine and ART-naïve groups, respectively (P ‫؍‬ 0.0002).

HIV-Positive Nigerian Adults Harbor Significantly Higher Serum Lumefantrine Levels than HIV-Negative Individuals Seven Days after Treatment for Plasmodium falciparum Infection

“…Our findings are consistent with those of Kredo et al (6) and confirm that drug-drug interactions between AL and NVP are potentially important. However, NVP stimulation of the CYP3A4 isoenzyme would be expected, a priori, to lower peripheral lumefantrine levels, due to an increase in the amount of lumefantrine metabolized to desbutyl-lumefantrine, a potent derivative that is normally found at a concentration between 0.5% and 5% of that of the parent compound at day 7 in the few studies available (8,20).…”

“…Our findings corroborate the findings of Kredo et al (6) in a larger group of AL-treated individuals, some of whom were infected with P. falciparum. Insufficient parasitological data were available to determine whether this difference in lumefantrine concentration provides any parasitological benefit to NVP-treated HIV patients with malaria infections.…”

“…Artemether is metabolized in the liver by the isoenzyme CYP3A4, to its active metabolite dihydroartemisinin (DHA), with peak plasma concentration being reached around 2 to 3 h after oral administration (4); elimination half-life is estimated at approximately 1 h. There is thus only limited opportunity for DHA to participate in drug-drug interactions. Lumefantrine is partially metabolized to desbutyl-lumefantrine, predominantly through CYP3A4, reaching peak plasma levels approximately 10 h after oral administration, and is then cleared slowly, showing a terminal half-life of 4 to 6 days in P. falciparum malaria cases (5)(6)(7)(8)(9). Oral bioavailability of lumefantrine is variable and highly dependent on administration with fatty foods (5,9,10).…”

Artemether-Lumefantrine Exposure in HIV-Infected Nigerian Subjects on Nevirapine-Containing Antiretroviral Therapy

“…The reported effects of nevirapine-based ART on lumefantrine exposure are variable (Table 2) (8,10,11,13,14,22). Our study reports ϳ50% lower lumefantrine exposure, consistent with findings reported from a Ugandan nonlinear mixed-effects modeling study (8,22).…”

“…The overall lower lumefantrine exposure may be due in part to a decrease in oral bioavailability resulting from increased intestinal P-glycoprotein or CYP3A4 expression or to the 30-to 60-min delay in food intake in the nevirapine-based ART group (23). While reported studies were all conducted with adults, there were differences in study design (parallel groups, crossover, or historical controls), pharmacokinetic analysis (intensive sampling, population modeling, or day 7 sampling only), sample size, patient characteristics (malaria infection status, race, ethnicity, and gender), and food intake that may underlie these differences (8,10,11,13,14,22,24).A significant limitation of our study is the use of healthy historical controls as the comparator group. While the sampling protocols were nearly identical and assays were conducted in the same laboratory, differences in demographic features, ethnicity, and HIV status between subjects enrolled in the control and nevirapine-based ART groups are important (16,18,25).…”