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HIV/AIDS Patients Display Lower Relative Bioavailability of Efavirenz than Healthy Subjects

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An Erratum to this article was published on 01 September 2011

Abstract

Background: Pharmacokinetic studies of antiretroviral drugs are often conducted in adult healthy subjects, and the results are extrapolated to HIV/AIDS patients. HIV/AIDS, however, is known to cause morphological and physiological changes that may alter the pharmacokinetics of antiretroviral drugs. We examined the effect of HIV/AIDS on the pharmacokinetics of efavirenz in Ugandans.

Methods: After a first oral dose of efavirenz 600 mg in treatment-naïve HIV-infected patients, blood samples were collected at nine time points up to 24 hours. The plasma-concentration time data from these patients were merged with previously reported data from adult healthy subjects. Population pharmacokinetic models were fitted to the data, using NONMEM VI software. Covariate analyses were performed to estimate the effects of HIV/AIDS disease, demographic characteristics (sex, bodyweight, age), biochemical variables (serum creatinine, urea, alanine aminotransferase) and pharmacogenetic variation in cytochrome P450 (CYP) 2B6, CYP3A5 and adenosine triphosphate-binding cassette, sub-family B, member 1 (ABCB1) on the population pharmacokinetic parameters.

Results: Efavirenz plasma concentration-time data obtained from 29 HIV-1-infected, treatment-naïve patients were merged with previously reported data from 32 adult healthy subjects. The model identified sex and HIV/AIDS disease as statistically significant categorical predictors of efavirenz pharmacokinetics. Females were predicted to have a 2-fold higher volume of distribution of the peripheral compartment after oral administration (V2/F) than males (95% CI 1.53,2.63), while HIV/AIDS patients were found to have 30% lower relative bioavailability (95% CI 18.7, 40.7) than healthy subjects. The increased V2/F in females resulted in a 2-fold longer elimination half-life than in males.

Conclusion: On the basis of the findings of this analysis, we conclude that, apart from bodyweight-based differences, both HIV/AIDS disease and sex affect efavirenz pharmacokinetics in Ugandans. HIV/AIDS disease is associated with reduced relative bioavailability of efavirenz. We recommend that findings from healthy subject studies be confirmed in HIV/AIDS patients and that caution be applied in direct extrapolation of exposure data to the target patient population.

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Acknowledgements

Jackson K. Mukonzo and Sarah Nanzigu contributed equally to this work.

This study was funded by Swedish International Development Cooperation Agency Department for Research Cooperation (SIDA/SAREC) grant nos. SWE 2004-098, HIV-2006-031 and SWE 2007-270; the Makerere University-Karolinska Institutet research collaboration; and European and Developing Countries Clinical Trials Partnership (EDCTP) grant no. CT.2005.32030.001.

Daniel Röshammar is an employee of AstraZeneca. However, this work was not funded or supported by any pharmaceutical company. All authors have no conflicts of interest that are directly relevant to the content of this study.

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Authors and Affiliations

  1. Division of Clinical Pharmacology, Department of Laboratory of Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, C-168, SE-141 86, Stockholm, Sweden

    Jackson K. Mukonzo, Sarah Nanzigu, Lars L. Gustafsson &  Eleni Aklillu

  2. Department of Pharmacology and Therapeutics, Faculty of Medicine, Makerere University, Kampala, Uganda

    Jackson K. Mukonzo, Sarah Nanzigu, Paul Waako & Jasper Ogwal-Okeng

  3. Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden

    Dinko Rekić & Michael Ashton

  4. AstraZeneca R&D, Mölndal, Sweden

    Daniel Röshammar

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  1. Jackson K. Mukonzo
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An erratum to this article is available at http://dx.doi.org/10.2165/11595800-000000000-00000.

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Mukonzo, J.K., Nanzigu, S., Rekić, D. et al. HIV/AIDS Patients Display Lower Relative Bioavailability of Efavirenz than Healthy Subjects. Clin Pharmacokinet 50, 531–540 (2011). https://doi.org/10.2165/11592660-000000000-00000

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