title: Steady state bioequivalence of generic and innovator formulations of stavudine, lamivudine, and nevirapine in HIV-infected Ugandan adults.
abstract: BACKGROUND
  Generic antiretroviral therapy is the mainstay of HIV treatment in resource-limited settings, yet there is little evidence confirming the bioequivalence of generic and brand name formulations. We compared the steady-state pharmacokinetics of lamivudine, stavudine and nevirapine in HIV-infected subjects who were receiving a generic formulation (Triomune) or the corresponding brand formulations (Epivir, Zerit, and Viramune).
  
  
  RESULTS
  An open-label, randomized, crossover study was carried out in 18 HIV-infected Ugandan subjects stabilized on Triomune-40. Subjects received lamivudine (150 mg), stavudine (40 mg), and nevirapine (200 mg) in either the generic or brand formulation twice a day for 30 days, before switching to the other formulation. At the end of each treatment period, blood samples were collected over 12 h for pharmacokinetic analysis. The main outcome measures were the mean AUC(0-12h) and C(max). Bioequivalence was defined as a geometric mean ratio between the generic and brand name within the 90% confidence interval of 0.8-1.25. The geometric mean ratios and the 90% confidence intervals were: stavudine C(max), 1.3 (0.99-1.71) and AUC(0-12h), 1.1 (0.87-1.38); lamivudine C(max), 0.8 (0.63-0.98) and AUC(0-12h), 0.8 (0.65-0.99); and nevirapine C(max), 1.1 (0.95-1.23) and AUC(0-12h), 1.1 (0.95-1.31). The generic formulation was not statistically bioequivalent to the brand formulations during steady state, although exposures were comparable. A mixed random effects model identified about 50% intersubject variability in the pharmacokinetic parameters.
  
  
  CONCLUSIONS
  These findings provide support for the use of Triomune in resource-limited settings, although identification of the sources of intersubject variability in these populations is critical.
authors.affiliation: Division of Epidemiology, School of Public Health, University of California Berkeley, Berkeley, California, United States of America.
authors.forename: Jayne
authors.initials: J
authors.lastname: Byakika-Tusiime
authors.forename: Leslie W
authors.initials: LW
authors.lastname: Chinn
authors.forename: Jessica H
authors.initials: JH
authors.lastname: Oyugi
authors.forename: Celestino
authors.initials: C
authors.lastname: Obua
authors.forename: David R
authors.initials: DR
authors.lastname: Bangsberg
authors.forename: Deanna L
authors.initials: DL
authors.lastname: Kroetz
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D018592:Cross-Over Studies; D016568:Drugs, Generic / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism; D015497:HIV-1; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010349:Patient Compliance; D018119:Stavudine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013810:Therapeutic Equivalency; D014454:Uganda
chemical_list: D019380:Anti-HIV Agents; D016568:Drugs, Generic; D015507:Drugs, Investigational; D019259:Lamivudine; D019829:Nevirapine; D018119:Stavudine