PI: F. Aweeka; Co-investigator: S. Parikh.
Start Date: June 2006; End Date: Ongoing
Funding: CFAR, Drug Research Unit, Novartis, Inc.
Antimalarial drugs are prone to clinically significant drug-drug interactions with antiretroviral drugs. The drugs are very complex pharmacologically in that they are substrates for cytochrome P450 (CYP) isozymes and generally require activation to active metabolites. Artemether-lumefantrine (AL) and amodiaquine/artesunate are widely used to treat malaria in Uganda. For HIV co-infected children and adults, artemether/lumefantrine is perhaps the most widely prescribed ACT drug due to limited adverse effects. This study includes three (3) components for evaluating potential drug-drug interactions in healthy HIV sero-negative volunteers. The project is based at UCSF and was initiated to provide information for the MU-UCSF studies. The first component evaluated the impact of efavirenz on amodiaquine/artesunate but was discontinued early due to unexpected hepatic toxicity in the first two subjects. The second component evaluated the effect of lopinavir/ritonavir on the disposition of artemether/lumefantrine. As ritonavir is a potent inhibitor of CYP3A4 and lumefantrine is metabolized by CYP3A4, a significant increase in lumefantrine exposure was expected. Indeed, results indicate that lumefantrine exposure increases 200% in the context of lopinavir/ritonavir co-administration. However, due to the excellent safety profile for artemether/lumefantrine, dosage adjustment is not recommended but increased safety monitoring is warranted. The third study is nearing completion and is evaluating the effect of efavirenz on the pharmacokinetics of artemether/lumefantrine. It is expected that efavirenz will lower lumefantrine exposure significantly due to its CYP3A4 induction effects.
1. German P, Greenhouse B, Coates C, Dorsey G, Rosenthal PJ, Charlebois E, Lindegardh N, Havlir D, Aweeka FT. Hepatotoxicity due to a drug interaction between amodiaquine plus artesunate and efavirenz. Clin Infect Dis. 2007 Mar 15;44(6):889-91.
2. German, P. Parikh S, Lawrence J, Lindegårdh, N, Rosenthal P, Havlir D, Charlebois E, Dorsey G, Aweeka FT. Lopinavir/ritonavir affects pharmacokinetic exposure of artemether/lumefantrine in HIV uninfected healthy volunteers. JAIDS, 2009 Aug 1;51(4):424-9.3.
3. German PI, Aweeka FT. Clinical pharmacology of artemisinin-based combination therapies. Clin Pharmacokinet. 2008;47(2):91-102.Clin Pharmacokinet. 2008;47(3):152.
4. German, P. Parikh S, Lawrence J, Lindegårdh, N, Rosenthal P, Havlir D, Charlebois, E. Dorsey G, Aweeka FT. Drug interaction between antimalarial drugs and lopinavir/ritonavir. F. Oral Presentation, 15th CROI, Boston, 2008. Abstract #132 (February 3-6).
Other: Huang L, Jayewardene AL, Li X, Marzan F, Lizak PS, Aweeka FT; Development and validation of a high-performance liquid chromatography/tandem mass spectrometry method for the determination of artemether and its active metabolite dihydroartemisinin in human plasma. J Pharm Biomed Anal. 2009 Jul 7