A Randomized Crossover Study to Determine Bioequivalence of Generic and Brand Name Nevirapine, Zidovudine, and Lamivudine in HIV-Negative Women in India

Abstract

Low-cost generic antiretroviral drugs are available in resource-limited settings for treatment of HIV infections. However, few bioequivalence data in specific populations in which these generics are likely to be used are available. We conducted a randomized crossover bioequivalence study of generic and brand name formulations of nevirapine, zidovudine, and lamivudine in HIV-negative Indian women using US Food and Drug Administration (FDA) criteria. Subjects took single doses of all formulations separated by a 14-day washout period. Plasma concentrations were measured over 96 hours during each study period. Average bioequivalence was determined using natural log-transformed maximum concentration (C(max)) and area-under-the-concentration-time curve (AUC) mean ratio data. Fifteen Indian women were enrolled. The 90% confidence intervals for nevirapine (14 subjects) and lamivudine (15 subjects) C(max), AUC from 0 to the last measurable time point (AUC(0-t)), and AUC from 0 to infinity (AUC(0-infinity)) mean ratios and zidovudine (15 subjects) AUC(0-t) and AUC(0-infinity) mean ratios were all within 0.80 to 1.25. However, the 90% confidence interval for zidovudine C(max) mean ratio was 0.70 to 1.46. Generic and brand name nevirapine and lamivudine met FDA average bioequivalence criteria. Lack of average bioequivalence for zidovudine was found for C(max) but is not expected to be clinically significant, because the total AUC values were similar between formulations.

A Chewable Pediatric Fixed-dose Combination Tablet of Stavudine, Lamivudine, and Nevirapine

“…However, 3TC in GPO-VIR S7 produced higher AUCs than the liquid formulation. Of interest, the AUC of 3TC in children taking GPO-VIR S7 (AUC 6.39 μ g h/mL) was closer to that of adults taking GPO-VIR S-30 (6.56 μ g h/mL)18 or to the 6.30–8.54 μ g.hr/mL reported in adult studies using 150 mg twice daily as an individual tablet or part of an FDC 19-21. Recently, a study of a pediatric FDC (d4T 6 mg, 3TC 30 mg, and NVP 50 mg) produced by Cipla and approved by WHO also found 3TC plasma concentrations comparable to those reported in adults,22 with mean 3TC AUC ranging from 4.14 to 6.76 μ g h/mL for children up to 30 kg.…”

Pharmacokinetics and Safety of a New Paediatric Fixed-Dose Combination of Zidovudine/Lamivudine/Nevirapine in HIV-Infected Children

“…The 3TC exposure reported in children using the branded tablet was 8.2 μg•h/ml and the tablet/liquid geometric mean ratio (90% CI) was 1.58 (1.37–1.81), both similar to the GPO-VIR Z30 FDC tablet in this study. It is important to note that the 3TC exposure with the paediatric FDC in Thai and branded tablets in African children are comparable to adult exposures following standard 150 mg twice daily dosing, which have been reported as 6.5 [23], 7.0 [24] and 8.5 μg•h/ml [25], as well as in older children taking branded 3TC tablets (6.5 μg•h/ml) [21] and other generic FDC tablets (range 4.2–6.8 μg•h/ml) [6]. The clear explanation for the difference in 3TC bioavailability between branded liquid and tablet formulations in children remains to be found.…”

Treatment simplification in HIV-infected adults as a strategy to prevent toxicity, improve adherence, quality of life and decrease healthcare costs

“…Several generic pharmaceutical manufacturers produce low priced FDCs for once- or twice-daily dosing3. Questions have been raised about the bioequivalence of such generic formulations, but so far published clinical trial data have been reassuring, and these generic FDCs are being approved by the US FDA for use in President’s Emergency Plan for AIDS relief (PEPFAR) programs in resource-limited settings 4,5…”

“…The generic coformulation of d4T/3TC/NVP is commonly used in sub-Saharan Africa, has been show to be highly effective, and costs about $20 per patient per month 5,49. In such settings, single-tablet, fixed-dose combinations improve the reliability and security of supplies, reduce the number of pills, simplify the dosing regimen, are easier to take, enhance adherence, reduce the potential for inappropriate sharing of drugs, ensure that the correct dosage of each component is taken 64…”