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The influence of nevirapine and efavirenz-based anti-retroviral therapy on the pharmacokinetics of lumefantrine and anti-malarial dose recommendation in HIV-malaria co-treatment

Maganda, B. A., Ngaimisi, E., Kamuhabwa, A. A., Aklillu, E. and Minzi, O. M. (2015) The influence of nevirapine and efavirenz-based anti-retroviral therapy on the pharmacokinetics of lumefantrine and anti-malarial dose recommendation in HIV-malaria co-treatment. Malaria Journal, 14 (1). ISSN 1475-2875

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Background: HIV-malaria co-infected patients in most parts of sub-Saharan Africa are treated with both artemether-lumefantrine (AL) and efavirenz (EFV) or nevirapine (NVP)-based antiretroviral therapy (ART). EFV, NVP, artemether and lumefantrine are substrates, inhibitors or inducers of CYP3A4 and CYP2B6, creating a potential for drug-drug interactions. The effect of EFV and/or NVP on lumefantrine pharmacokinetic profile among HIV-malaria co-infected patients on ART and treated with AL was investigated. Optimal lumefantrine dosage regimen for patients on EFV-based ART was determined by population pharmacokinetics and simulation.
Methods: This was a non-randomized, open label, parallel, prospective cohort study in which 128, 66 and 75 HIV-malaria co-infected patients on NVP-based ART (NVP-arm), EFV-based ART (EFV-arm) and ART naïve (control-am) were enrolled, respectively. Patients were treated with AL and contributed sparse venous plasma samples. Pharmacokinetic analysis of lumefantrine was done using non-linear mixed effect modelling.
Results: Of the evaluated models, a two-compartment pharmacokinetic model with first order absorption and lag-time described well lumefantrine plasma concentrations time profile. Patients in the EFV-arm but not in the NVP-arm had significantly lower lumefantrine bioavailability compared to that in the control-arm. Equally, 32% of patients in the EFV-arm had day-7 lumefantrine plasma concentrations below 280 ng/ml compared to only 4% in the control-arm and 3% in the NVP-arm. Upon post hoc simulation of lumefantrine exposure, patients in the EFV-arm had lower exposure (median (IQR)) compared to that in the control-arm; AUC0-inf; was 303,130 (211,080–431,962) versus 784,830 (547,405–1,116,250); day-7 lumefantrine plasma concentrations was: 335.5 (215.8-519.5) versus 858.7 (562.3-1,333.8), respectively. The predictive model through simulation of lumefantrine exposure at different dosage regimen scenarios for patients on EFV-based ART, suggest that AL taken twice daily for five days using the current dose could improve lumefantrine exposure and consequently malaria treatment outcomes.
Conclusions: Co-treatment of AL with EFV-based ART but not NVP-based ART significantly reduces lumefantrine bioavailability and consequently total exposure. To ensure adequate lumefantrine exposure and malaria treatment success in HIV-malaria co-infected patients on EFV-based ART, an extension of the duration of AL treatment to five days using the current dose is proposed.

Item Type: Article
Keywords: Malaria-HIV, Efavirenz, Nevirapine, Lumefantrine, Drug-drug interactions
Subjects: HIV > Prevention
Malaria > Diagnosis & treatment
Divisions: Muhimbili University of Health and Allied Sciences (MUHAS)
Depositing User: Digital Library Manager
Date Deposited: 02 Jun 2015 06:19
Last Modified: 02 Jun 2015 06:19

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