Drug Interaction Between Coartem® and Nevirapine, Efavirenz or Rifampicin in HIV Positive Ugandan Patients

Study Description

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Brief Summary:

There are increasing numbers of HIV-infected patients in sub-Saharan Africa receiving antiretroviral drugs and/or rifampicin based antituberculous therapy. HIV infected patients are at an increased risk of contracting malaria. Increasing resistance to anti-malarials such as chloroquine, amodiaquine, fansidar, sulphadoxine-pyrimethamine in East and West Africa has led the WHO to recommend artemether-lumefantrine (Coartem®- Novartis) as first line therapy for malaria for adults and children. As early as 2004, fourteen countries in sub-Saharan Africa had adopted this guideline as national policy.

There are no data on the interaction between Coartem® and any of the antiretroviral agents. Both components of Coartem® are substrates for the 3A4 isoform of cytochrome P450. Despite the lack of data, antiretroviral drugs and/or antituberculous drugs in addition to Coartem® are of necessity co-prescribed daily in the African setting. Nevirapine, efavirenz and rifampicin are known inducers of cytochrome P450 3A4. A technical consultation convened by WHO in June, 2004 concluded that additional research on interactions between antiretroviral and antimalarial drugs is urgently needed.

We propose to perform a suite of pharmacokinetic studies to evaluate these interactions in HIV infected Ugandan patients. The aim of these studies is to evaluate the pharmacokinetic interaction between Coartem® and commonly co-prescribed inducers of 3A4 i.e. nevirapine, efavirenz and rifampicin.

1. Comparison of steady state pharmacokinetics of Coartem® in HIV-infected patients prior to commencement of nevirapine and at nevirapine steady state
2. Comparison of steady state pharmacokinetics of Coartem® in HIV-infected patients prior to commencement of efavirenz and at efavirenz steady state
3. Comparison of steady state pharmacokinetics of Coartem® in Ugandan patients at rifampicin steady state and without rifampicin

Condition or disease	Intervention/treatment	Phase
HIV Infections; Tuberculosis	Drug: Lumefantrine-artemether and nevirapine; Drug: lumefantrine-artemether and efavirenz; Drug: Lumefantrine-artemether and rifampicin	Phase 4

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Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	90 participants
Allocation:	Non-Randomized
Intervention Model:	Crossover Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Pharmacokinetic Interaction Between Coartem® and Either Nevirapine, Efavirenz or Rifampicin in HIV Positive Ugandan Patients
Study Start Date :	February 2008
Estimated Primary Completion Date :	July 2011
Estimated Study Completion Date :	July 2011

Arms and Interventions

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Arm	Intervention/treatment
Experimental: 1; nevirapine arm	Drug: Lumefantrine-artemether and nevirapine; Administration of lumefantrine 480mg co-formulated with artemether 80mg twice daily for three days to HIV positive patients receiving nevirapine 200mg twice daily as part of their antiretroviral treatment; Other Names: Coartem; Triomune
Experimental: 2; efavirenz arm	Drug: lumefantrine-artemether and efavirenz; Administration of lumefantrine 480mg co-formulated with artemether 80mg twice daily for three days to HIV positive adults receiving efavirenz tablets 600mg once daily; Other Names: Coartem; Sustiva
Experimental: 3; Rifampicin arm	Drug: Lumefantrine-artemether and rifampicin; Administration of lumefantrine 480mg co-formulated with artemether 80mg twice daily for three days to patients receiving rifampicin as part of fixed dose combination therapy for tuberculosis; Other Name: Coartem

Outcome Measures

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Primary Outcome Measures :

1. Pharmacokinetics of lumefantrine in patients receiving either nevirapine, efavirenz or rifampicin [ Time Frame: 11 months ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 60 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Age over eighteen years
• Ability to provide full written informed consent
• Confirmed diagnosis of HIV infection

Exclusion Criteria:

• Haemoglobin < 8g/dl
• 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 (information will be obtained from patients' medication history through interview with the patient)
• Abnormal EKG ie QTc (Rate adjusted QT interval) >450ms (men) or >470ms (women)
• Intercurrent Illness including malaria
• Known hypersensitivity to artemisinin-derivatives, halofantrine or lumefantrine
• History of cardiac disease

Contacts and Locations

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Locations

Uganda
Infectious Diseases Institute, Makerere University
Kampala, Uganda, 22418

Sponsors and Collaborators

Makerere University

Health Research Board, Ireland

Investigators

Principal Investigator:	Concepta Merry, PhD	Trinity Colleg Dublin

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Hoglund RM, Byakika-Kibwika P, Lamorde M, Merry C, Ashton M, Hanpithakpong W, Day NP, White NJ, Äbelö A, Tarning J. Artemether-lumefantrine co-administration with antiretrovirals: population pharmacokinetics and dosing implications. Br J Clin Pharmacol. 2015 Apr;79(4):636-49. doi: 10.1111/bcp.12529.

Responsible Party:	Concepta Merry, Infectious Diseases Institute, Makerere University
ClinicalTrials.gov Identifier:	NCT00620438 History of Changes
Other Study ID Numbers:	CPR 005
First Posted:	February 21, 2008
Last Update Posted:	December 6, 2010
Last Verified:	December 2010

Keywords provided by Makerere University:

Lumefantrine; Efavirenz; Nevirapine; Rifampicin; HIV

Additional relevant MeSH terms:

HIV Infections; Tuberculosis; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Efavirenz	Nevirapine; Rifampin; Lumefantrine; Artemether; Artemether-lumefantrine combination; Artemisinins; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 Enzyme Inhibitors