Coadministration of artemether/lumefantrine (80/480 mg, given at 0, 8, 24, 36, 48 and 60 h) with lopinavir/ritonavir was studied in HIV positive, malaria negative patients in a parallel study (n=18 control group; n=16 lopinavir/ritonavir group). After adjusting for mg/kg dose, median day-7 lumefantrine concentrations were almost 10-fold higher in the lopinavir than the antiretroviral-naive group (3170 vs 336 ng/mL), with AUC and Cmax increasing 4.82-fold (2478 vs 445 μg.h/mL) and 2.67-fold (28.2 versus 8.8 μg/mL), respectively. ECG monitoring showed there was no increase in PR or QTcF, even at maximal lumefantrine concentration. For artemether, there were no significant differences between treatment groups for any of the pharmacokinetic parameters at either of the time periods studied. Dihydroartemisinin (active metabolite) AUC and Cmax both increased by 73% after dose 1 (0-8h) and by 12% and 19%, respectively, after dose 6 (60-68 h). The authors conclude that despite the increase in lumefantrine concentrations, no safety concerns were revealed for coadministration of artemether/lumefantrine and lopinavir/ritonavir. 

Artemether, dihydroartemisinin and lumefantrine concentrations were determined in a group of HIV-negative children (n=51-54, depending on PK parameter) and in a group of HIV-positive children on lopinavir/ritonavir-based ART. With lopinavir/ritonavir (n=30), AUC and Cmax of artemether both decreased by 25%, and AUC and Cmax of dihydroartemisinin decreased by 19% and 17%; lumefantrine AUC and Cmax increased by 114% and 54%. 

Coadministration of artesunate + mefloquine (200 mg daily + 750 mg day 1, 500 mg day 2) and lopinavir/ritonavir (400/100 mg twice daily) was studied in 16 HIV-positive Thai subjects. Artesunate Cmax and AUC increased by 59% and 52%, but dihydroartemisinin Cmax and AUC decreased by 37% and 49%. Mefloquine Cmax and AUC decreased by 13% and 25%. Lopinavir Cmax and AUC decreased by 23% and 38%; ritonavir Cmax and AUC decreased by 52% and 54%. The 90% CI of the geometric mean ratio (GMR) of AUC and Cmax were outside the acceptable bioequivalent range for each drug. The authors conclude that the reduction in systemic exposure of all investigated drugs raises concerns of an increased risk of treatment failure rate in co-infected patients and should be further investigated.

Data from two clinical studies, investigating the influence of the HIV drugs efavirenz, nevirapine and lopinavir/ritonavir on the pharmacokinetics of the antimalarial drugs lumefantrine, artemether and their respective metabolites, in HIV infected patients were pooled and analyzed using a non-linear mixed effects modelling approach. Efavirenz and nevirapine significantly decreased lumefantrine exposure by ~70% and ~25% respectively while lopinavir/ritonavir substantially increased lumefantrine exposure (increase of 439%). All antiretroviral drugs decreased the total exposure to dihydroartemisinin (decrease of 71.7%, 41.3% and 59.7% for efavirenz, nevirapine and ritonavir/lopinavir, respectively). Simulations suggest that a substantially increased artemether-lumefantrine dose is required to achieve equivalent exposures when co-administered with efavirenz (250% increase) and nevirapine (75% increase). When co-administered with lopinavir/ritonavir it is unclear if the increased lumefantrine exposure compensates adequately for the reduced dihydroartemisinin exposure and thus whether dose adjustment is required.

Coadministration of artemether/lumefantrine (80/480 mg single dose) and lopinavir/ritonavir (400/100 mg twice daily) was studied in two groups of HIV-infected Ugandan subjects. When compared to the control group (n=16), artemeter exposure was significantly decreased in the lopinavir/ritonavir group (n=13); median Cmax decreased from 112 ng/ml to 56 ng/ml and median AUC decreased from 271 ng.h/ml to 162 ng.h/ml. There was no significant effect on dihydroartemisinin Cmax (66 vs 73 ng/ml) or AUC (217 vs 180 ng.h/ml). Lumefantrine Cmax and AUC increased during coadministration (2532 vs 7097 ng/ml, 46925 vs 267386 ng.h/ml).

The coadministration of lopinavir/ritonavir (400/100 twice daily) and the antimalarial drugs artemether/lumefantrine (80/480 mg twice daily) was studied in 10 HIV- subjects. The addition of lopinavir/ritonavir significantly increased lumefantrine AUC by 2.3-fold and there was trend towards increased Cmax (1.4-fold). Trends towards decreased AUC (39%) and Cmax (22%) were observed with artemether pharmacokinetics, whilst there was a significant decrease in the AUC and Cmax (45% and 36%, respectively) of the active metabolite dihydroartemisinin. Pharmacokinetics of lopinavir were not significantly altered and there was a non-significant increase in ritonavir exposure. The authors conclude that the results suggest the coadministration of artemether/lumefantrine and lopinavir/ritonavir can be carried out safely, though a formal safety analysis should be addressed in coinfected subjects.