JAC Advance Access originally published online on July 18, 2008
Journal of Antimicrobial Chemotherapy 2008 62(5):1113-1117; doi:10.1093/jac/dkn290
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Original research |
Steady-state pharmacokinetic comparison of generic and branded formulations of stavudine, lamivudine and nevirapine in HIV-infected Ugandan adults
1 Research Department, Makerere University Infectious Diseases Institute, Kampala, Uganda 2 Department of Pharmacology and Therapeutics, Trinity College, Dublin, Ireland 3 Infectious Diseases Network for Treatment and Research in Africa (INTERACT), Kampala, Uganda 4 Department of Infectious Diseases, University of Turin, Turin, Italy 5 Department of Pharmacology, University of Liverpool, Liverpool, UK 6 St Stephen's AIDS Centre Pharmacokinetics Research Unit, London, UK
Received 3 April 2008; returned 23 April 2008; revised 18 June 2008; accepted 19 June 2008
* Corresponding author. Tel: +256-772-626885; E-mail: pbyakika{at}idi.co.ug
Background: We aimed to compare the steady-state pharmacokinetic parameters and tolerability of Triomune 40® (stavudine 40 mg, lamivudine 150 mg and nevirapine 200 mg) and branded formulations of these drugs in HIV-infected Ugandans.
Methods: This includes a randomized, open-label, cross-over study of HIV-infected patients stable on therapy for 1 month. Patients were randomized to generic or branded formulation. Plasma pharmacokinetics were assessed after 1 month. The following day, alternate formulation was administered, and 1 month later, drug pharmacokinetics were re-assessed. Plasma pharmacokinetics were determined using HPLC–UV detection. Similarity between steady-state pharmacokinetic parameters was assessed using the US Food and Drug Administration standards for bioequivalency testing. Tolerability was assessed using questionnaires.
Results: Sixteen (10 females) patients completed the study. Median (IQR) age, weight and CD4 count were 37 (33.7–40) years, 65 (63.4–66) kg and 292 (220.7–344.5) cells/mm3, respectively. All patients received co-trimoxazole. The geometric mean ratio (90% CI) for stavudine, lamivudine and nevirapine was 0.92 (0.78–1.08), 1.11 (0.95–1.30) and 0.84 (0.64–1.11), respectively, for Cmax, and 0.83 (0.70–0.97), 1.06 (0.94–1.20) and 0.88 (0.71–1.10), respectively, for AUC. Stavudine plasma concentrations were significantly lower for the generic formulation. Pharmacokinetic parameter inter-individual variability ranged from 29% to 99%. There were no differences in tolerability for the two formulations.
Conclusions: Pharmacokinetic profiles of generic and branded drugs were similar. Differences particularly with regard to stavudine were demonstrated. Surveillance of the quality of generic antiretroviral drugs in the target populations is needed. Capacity building for pharmacokinetic research in resource-limited settings is a priority.
Keywords: antiretroviral drugs , PK , Uganda