Abacavir/lamivudine/zidovudine as a combined formulation tablet: Bioequivalence compared with each component administered concurrently and the effectof food on absorption

A single-center, open-label, three-way crossover study was conducted in 24 healthy subjects 50 assess (1) the bioequivalence of a combined abacavir 30 0 mg/lamivudine 150 mg/zidovudine 300 mg (A/L/Z) combination tablet relativ e to the separate brand-name components administered simultaneously and (2) the effect of food on the bioavailability of the drugs from the combinatio n tablet. The subjects were randomly assigned to receive each of the follow ing three treatments, separated by a a-day washout period: one A/L/Z combin ation tablet after an overnight fast, one abacavir 300 mg tablet + one lami vudine 150 mg tablet + one zidovudine 300 mg tablet sequentially after on o vernight fast, or one A/L/Z combination tablet 5 minutes after completing a standardized high-fat breakfast (67 g fat, 58 g carbohydrate, and 33 g pro tein). Serial blood samples were collected up to 24 hours postdose for dete rmination of abacavir, lamivudine, and zidovudine serum concentrations, Sta ndard pharmacokinetic parameters were estimated. Treatments were considered bioequivalent if 90% confidence intervals (CI) for geometric least squares (GLS) mean ratios for abacavir, lamivudine, and zidovudine area under the serum concentration-time curve (AUC(infinity)) and maximum observed serum c oncentration (C-max) fell entirely within 0.80 to 1.25 for log-transformed parameters. The combined A/L/Z tablet was bioequivalent in the extent (AUC( infinity)) and rate of absorption (C-max and time of C-max [t(max)]) to the individual brand-name drug components administered concurrently under fast ed conditions. GLS ratios and 90% CI for AUC(infinity) and C-max were 0.99 (0.96, 1.03) and 1.00 (0.90, 1.11), respectively, for abacavir; 0.95 (0.91, 0.99) and 0.90 (0.84, 0.99), respectively for lamivudine; and 0.95(0.89, 1 .02)and 0.96 (0.80, 1.15), respectively, for zidovudine. The extent of abso rption of abacavir, lamivudine, and zidovudine from the combination tablet was not altered by administration with meals, indicating that this formulat ion may be administered with or without food. However, food slowed the rate of absorption, delayed the t(max), and reduced the C-max of abacavir, lami vudine, and zidovudine. These changes, which were consistent with those obs erved with the individual reference formulations when administered with foo d, were nor considered clinically important. All formulations were well tol erated under fasted and fed conditions. Journal of Clinical Pharmacology, 2 001;41:277-288 (C) 2001 the American College of Clinical Pharmacology.