Background:  Malaria infection results in 300 million to 500 million cases and 1.5 million to 2.7 million deaths annually. Malaria therapy has changed greatly in recent years, with implementation of artemisinin (AR) -based combination therapy (ACT) to circumvent drug resistance. Coartem (artemether/lumefantrine (LR)), a leading ACT, is currently adopted by >60 countries for treatment of uncomplicated malaria. Both drugs are metabolized via cytochrome P450 (CYP) 3A4 and are susceptible to complex interactions with antiretrovirals (ARV) when used in HIV-infected patients with malaria. We evaluated the pharmacokinetics of LR and lopinavir/ritonavir (LPV/r) during concomitant therapy.

Methods:  HIV-1-uninfected healthy volunteers received a standard 3-day regimen of AR/LR 80/480 mg twice daily (study days [SD] 1 to 4) followed by LPV/r 400/100 mg twice daily alone (SD 16 to 41) and with another 3-day regimen of AR/LR (SD 28 to 31). Study drugs were taken with a high fat meal to optimize absorption. Serial LR plasma concentrations (C) were measured over 264 hours on SD 4 to 15 (alone) and 31 to 42 (with LPV/r). LPV/r C were measured over 12 hours on SD 26 (alone) and 31 (with AR/LR). LR AUC_0-inf (h·μg/mL), LPV/r steady-state AUC_0-12(h·μg/mL), maximum C (C_max), and last observed C or trough C (C_last  to LR_, C_trough—LPV/r) were estimated. Statistical analysis was performed using Wilcoxon signed-rank test.

Results:  We enrolled 10 subjects (4 females, 6 males). The addition of LPV/r to AR/LR resulted in increases in LR AUC_(0-inf) (193% ↑), C_last  (298%↑), and LR C_max. LPV/r AUC, C_max, and C_trough parameters in the setting of AR/LR were similar to parameters for LPV/r alone. Study treatments were well tolerated by all subjects.

Conclusions:  LPV/r co-administration resulted in significant but highly variable increases in LR AUC and C_last, presumably due to inhibition of CYP3A4. The increase in AUC should be considered in the context of the excellent safety profile for LR and high levels previously reported in malaria patients. The increase may also be beneficial, as LR exposure has been correlated with treatment response. These data suggest that AR/LR may be co-administered with LPV/r without dose adjustment.