The overwhelming majority of HIV-infected persons reside in the developing world. As such, recent efforts have focused on providing antiretroviral pharmacotherapy to this population. However, there are a number of factors indigenous to non-Western HIV-infected patients that may alter their virologic, immunologic, and/or toxicologic response to antiretroviral therapy. Absorption, distribution, and clearance of antiretroviral medications may differ among patients residing in non-Western countries secondary to dietary influences, parasitic infection, and malabsorption. Genetic polymorphisms of drug metabolizing enzymes (cytochrome P450; CYP) and drug transporters (i.e. P-glycoprotein) as well as generic formulations of antiretroviral medications may also contribute to altered pharmacokinetics among these patients. The purpose of this pilot, hypothesis-generating study is (1) to characterize the pharmacokinetics of the non-nucleoside reverse transcriptase inhibitor nevirapine in a non-Western HIV-infected population (Kampala, Uganda) and in a similar cohort of HIV-infected individuals in the United States and (2) to compare pharmacokinetic parameter values between the groups. Twenty-five subjects from each site will participate. Subjects from the Ugandan site may participate regardless of their CD4+ lymphocyte count and viral load; they will be studied prior to the U.S. cohort. The U.S. group will be selected to include subjects that are demographically similar to their Ugandan counterparts. Subjects will have one pre-dose and two post-dose blood samples collected for the determination of nevirapine plasma concentrations. Samples will be analyzed using LC/MS-MS. Population pharmacokinetic parameter values (Cmax, Cmin, AUC, CL/F, Vd) will be determined using NONMEM and compared between groups. Blood samples collected during the study may also be used to determine CYP and MDR1 genotypes of study subjects in an effort to explain any observed differences in pharmacokinetic parameter values between the study populations. This human study should begin in the first quarter of 2005. In a first phase of assuring comparability of products, tablets containing nevirapine (from 6 international sources representing 3 manufacturers) were assayed for drug content and all were found to contain the labeled amount of drug (200 mg); these results were presented at two international meetings as well as in the Journal of the American Medical Association (JAMA). A second report describing the content of medications (other than nevirapine-containing products) obtained from developing countries was recently reported in the journal Clinical Infectious Diseases.
| Penzak, S R; Kabuye, G; Mugyenyi, P et al. (2007) Cytochrome P450 2B6 (CYP2B6) G516T influences nevirapine plasma concentrations in HIV-infected patients in Uganda. HIV Med 8:86-91 |
| Penzak, Scott R; Acosta, Edward P; Turner, Michele et al. (2004) Antiretroviral drug content in products from developing countries. Clin Infect Dis 38:1317-9 |
| Penzak, Scott R; Acosta, Edward P; Turner, Michele et al. (2003) Analysis of generic nevirapine products in developing countries. JAMA 289:2648-9 |
