Drug Interaction Study Between Lumefantrine and Lopinavir/Ritonavir

• Status: Completed
• Trial end date: 2008-12-01
• Target enrollment: 0
• Participant gender: All

Summary

With the roll out of antiretroviral therapy (ARV) for HIV across sub-Saharan Africa an unprecedented number of people will be commencing lifelong therapy. Current estimates are that 5-6 million people in sub-Saharan Africa require ART. At the same time, the World Health Organization (WHO) Roll Back Malaria campaign is aggressively promoting the use of artemether/lumefantrine as first-line therapy for malaria in this setting. Many patients in this setting have already become resistant to first-line ARV and have moved onto lopinavir/ritonavir (Kaletra) based second-line regimens. Kaletra is a potent inhibitor of Cytochrome P450 3A4 (CYP 3A4), an enzyme responsible for the metabolism of many drugs which is found predominantly in the liver and the gut. Lumefantrine, and to a lesser extent artemether, is extensively metabolized by CYP 3A4. Therefore when given to a patient already taking Kaletra for HIV, it is likely that elevated levels of these drugs in the patient will result. There is some concern that lumefantrine may be cardiotoxic due to its structural similarity to halofantrine which is known to cause irregular heart rhythms. This has not been borne out as yet in any studies performed with lumefantrine, however it is not known what levels will be achieved in patients when it is administered with a protease inhibitor such as Kaletra. The WHO has not addressed this issue in any of its previous policy documents but has identified ARV-antimalarial drug interaction studies as a research priority. This single dose pharmacokinetic (PK) study aims to compare the levels of lumefantrine/artemether that result when it is given to a patient on Kaletra with patients not on any ARV. Data generated by this study will help address this important knowledge gap which has been identified by WHO and others as meriting urgent investigation.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Makerere University
• Collaborator: University of Liverpool
• Treatments: Artemether; Artemether-lumefantrine combination; Artemether, Lumefantrine Drug Combination; Lopinavir; Lumefantrine; Ritonavir

Criteria

Inclusion Criteria:

• Age over eighteen

• Ability to provide full informed written consent

• Confirmed diagnosis of HIV infection

Exclusion Criteria:

• Haemoglobin < 8 g/dl

• HIV RNA (Viral Load) > 400 c/ml (if on antiretroviral therapy)

• Malaria Parasitaemia

• Liver and renal function tests > 3 times the upper limit of normal

• Pregnancy

• Use of known inhibitors or inducers of cytochrome P450 or P-glycoprotein

• Use of herbal medications

• QTc (Rate adjusted QT interval) > 450 ms (men) or > 470 ms (women)

• Intercurrent illness including malaria