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Single-Dose Bioequivalence of a New Fixed-Dose Combination Tablet Containing Tenofovir Disoproxil Fumarate and Lamivudine

Feleder Ethel C, Yerino Gustavo A, Halabe Emilia K, Carla Serebrinsky, Soledad Gonzalez and Zini Elvira

Tenofovir Disoproxil Fumarate, CAS 147127-20-6 is a nucleotide reverse transcriptase inhibitor with potent activity against both HIV and hepatitis B infections. Lamivudine, CAS 134678-17-4 is a nucleoside analogue reverse transcriptase inhibitor developed as a treatment for HIV infection and also with activity against hepatitis B virus. The combination of tenofovir and lamivudine associated either with non-nucleoside reverse transcriptase inhibitors or with a ritonavir-boosted or unboosted protease inhibitor are recommended as preferred regimens for antiretroviral therapy-naïve patients infected with HIV, and also for the treatment of HIV-HVB coinfected patients. The objective of this study was to compare rate and extent of absorption and to assess the bioequivalence between a new pharmaceutical equivalent tablet formulation containing a fixed-dose combination of tenofovir disoproxil fumarate/ lamivudine 300/300 mg and the innovator products. A randomized, single-center, open-label, single-dose, two-way crossover bioequivalence study in 40 healthy adult subjects was conducted. Dosing was separated by a wash-out period of 14 days. All subjects signed an informed consent form. In each study period, 13 blood samples were collected in Vacutainers containing EDTA over 48 h. Plasma levels of tenofovir and lamivudine were determined by a validated HPLC/fluorescence assay and by a validated HPLC/UV assay, respectively. Rate and extent of absorption were similar between products. The 90% confidence interval(CI) of the ratio of the geometric means for log-transformed C max , AUC last and AUC inf values were used to assess bioequivalence between the two formulations using the equivalence interval of 80 and 125%. In healthy subjects, the point estimate and 90 % C I of the ratios of C max , AUC last and AUC inf values for tenofovir were 100.99%(92.89-109.80%), 96.11%(90.02-102.63%) and 94.73%(88.22-101.73%), respectively; and for lamivudine were 90.37%(83.76-97.50%), 97.02%(93.27-100.93%) and 97.04%(93.41-100.82%), respectively. Both treatments exhibited similar tolerability and safety. It was concluded that the new pharmaceutical formulation was bioequivalent to the innovators.