The concomitant administration of drugs and antimalarial drugs is recommended for the treatment of HIV (Human Immunodeficiency Virus) patients with malaria resulting in drug-drug interactions (DDI) causing either lack of efficacy or toxicities. Drug metabolism is often the first step in understanding the DDI potential of either a new chemical entity or a combination of drugs. inhibitor (PI) such as is a potent CYP 3A4 inhibitor and may interact with these antimalarial drugs that are metabolized by CYP3A4 to cause metabolism-related DDI's. the present study is an attempt to evaluate the potential for a drug-drug interaction between and through metabolic stability studies. Metabolic stability of antimalarial and drugs alone and in combination with and without and was evaluated using human liver (HLM). The antimalarial drugs , and were metabolically unstable alone (% metabolism ≥ 80%) and in combination with other antimalarial drugs in HLM. , and were metabolically stable (% metabolism ≤ 30%). drug was metabolically unstable while was moderately stable. intrinsic clearance of antimalarial drugs , and decreased from 106.4, 290.6 and 230 ml/min/kg to 32, 44.8 and 49.5 ml/min/kg in the presence of . However, there was no change in the intrinsic clearance of , and in the presence of . did not alter the clearance of antimalarial drugs. This study suggests that affected the clearance of a few antimalarial drugs in HLM probably by the inhibition of CYP3A4 and findings may need to be further evaluated in clinical studies.

The current treatment for Human Immunodeficiency Virus (HIV) patients coinfected with malaria involves the coadministration of antimalarial and antiretroviral (ARV) drugs. The World Health Organization (WHO) recommends artemisinin-based therapy for malaria that usually consists of artemether, artesunate or dihydroartemisinin with non-artemisinin derivatives such as amodiaquine, lumefantrine and mefloquine.  Protease inhibitors (PI) such as ritonavir contribute to the improved health of HIV-positive individuals, and the inclusion of ritonavir in antiretroviral regimens is common in clinical practice. Ritonavir is a potent inhibitor of human CYP3A4, which is the primary enzyme involved in the metabolism of many of artemisinin-based drugs, as well as amodiaquine and proguanil.  Upon co-administration, ritonavir can potentially influence the metabolism and thus increase the systemic exposure of these drugs. In order to understand this pharmacokinetic (PK) drug interaction, the current work evaluated the effect of ritonavir (50 mg/kg orally) on the PK of antimalarial drug combinations in Sprague Dawley (SD) rats. When co-administered with ritonavir, the exposure (AUC) of the antimalarial drugs artemether, artesunate and proguanil was increased by approximately 3.5-fold. Correspondingly, peak plasma concentrations (Cmax) of these drugs increased as well. There was no apparent influence of ritonavir on the PK of lumefantrine, amodiaquine and atovaquone. This study demonstrates the potential influence of ritonavir on the pharmacokinetics of at least some anti-malarial drugs, likely a result of inhibition of CYP3A. Further evaluation of clinically relevant drug interaction in humans may be warranted to ensure safe and effective use of anti-malarial and anti-HIV drugs concomitantly.