Lamivudine zidovudine as a combined formulation tablet: Bioequivalence compared with lamivudine and zidovudine administered concurrently and the effect of food on absorption

A single-center, open-label, three-way crossover study was conducted in 24 healthy subjects to assess (2) the bioequivalence of a combined lamivudine 150 mg/zidovudine 300 mg tablet relative to the separate brand-name compone nts administered concurrently and (2) the effect of food on the bioavailabi lity of the drugs from the combination tablet. The subjects were randomly a ssigned to receive each of the following three treatments, separated by a 5 - to 7-day washout period: one lamivudine/zidovudine combination tablet aft er an overnight fast, one lamivudine 150 mg tablet and one zidovudine 300 m g tablet simultaneously after an overnight fast, or one lamivudine/zidovudi ne combination tablet 5 minutes after completing a standardized high-fat br eakfast (67 g fat, 58 g carbohydrate, and 33 g protein). Serial blood sampl es were collected up to 24 hours postdose for the determination of lamivudi ne and zidovudine plasma concentrations. Standard pharmacokinetic parameter s were estimated. Treatments were considered bioequivalent if 90% confidenc e intervals for the ratio of least squares (LS) means for the lamivudine an d zidovudine area under the plasma concentration-time curve (AUC(m)) and ma ximum observed plasma concentration (C-max) fell entirely within 0.80 to 1. 25 for log-transformed parameters. The combined lamivudine/zidovudine table t was bioequivalent in the extent (AUC(m)) and rate of absorption (C-max an d time of C-max [t(max)]) to the individual brand-name drug components admi nistered concurrently under fasted conditions. Geometric LS mean ratios and 90% confidence intervals for AUC(infinity) and C-max were 0.97 (0.92, 1.03 ) and 0.94 (0.84, 1.06), respectively, for lamivudine and 0.99 (0.91, 1.07) and 0.97 (0.82, 1.15), respectively for zidovudine. The extent of absorpti on of lamivudine and zidovudine from the combination tablet was not altered by administration with meals, indicating that this formulation may be admi nistered with or without food However, food slowed the rate of absorption, delayed the t(max), and reduced the C-max of lamivudine and zidovudine. The se changes were not considered clinically important. All formulations were well tolerated under fasted and fed conditions. (C) 1999 the American Colle ge of Clinical Pharmacology.