Evaluation of metabolic stability of antimalarial and antiretroviral drugs

Abstract

The concomitant administration of antiretroviral drugs and antimalarial drugs is recommended for the treatment of HIV (Human Immunodeficiency Virus) patients coinfected 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. Protease inhibitor (PI) such as ritonavir is a potent CYP 3A4 inhibitor and may interact with these antimalarial drugs that are metabolized by CYP3A4 to cause metabolism-related DDI's. Hence the present study is an attempt to evaluate the potential for a drug-drug interaction between antimalarials and antiretrovirals through invitro metabolic stability studies. Metabolic stability of antimalarial and antiretroviral drugs alone and in combination with and without ritonavir and lopinavir was evaluated using human liver microsomes (HLM). The antimalarial drugs artemether, artesunate and amodiaquine were metabolically unstable alone (% metabolism ≥ 80%) and in combination with other antimalarial drugs in HLM. Lumefantrine, atovaquone and proguanil were metabolically stable (% metabolism ≤ 30%). Antiretroviral drug lopinavir was metabolically unstable while ritonavir was moderately stable. In-vitro intrinsic clearance of antimalarial drugs artemether, artesunate and amodiaquine 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 ritonavir. However, there was no change in the in-vitro intrinsic clearance of lumefantrine, atovaquone and proguanil in the presence of ritonavir. Lopinavir did not alter the clearance of antimalarial drugs. This study suggests that ritonavir 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.