Bioequivalence studies of two different film-coated tablet formulations of valacyclovir of two different strengths in healthy volunteers

These studies were conducted in order to assess the bioequivalence of two film-coated formulations containing 250 mg and 1000 mg of valacyclovir (INN: valaciclovir; CAS 124832-26-4), which is the L-valyl ester and a pro-drug of the antiviral drug acyclovir (INN: aciclovir). In the study with valacyclovir 250 mg, 36 healthy subjects were enrolled in a randomized, single-dose, open-label, 2-way crossover study, with a washout period of 10 days. In the study with valacyclovir 1000 mg, 46 healthy subjects were enrolled in a randomized, single-dose, open-label, 2-way crossover study, with a washout period of 7 days. Plasma samples were collected up to 36 h post-dose for both studies. Valacyclovir levels were determined by liquid chromatography with tandem mass detection (ie, the LC/MS/MS method) (lower limit of quantification: 0.50 ng/mL for valacyclovir and 9.93 ng/mL for acyclovir for the 250 mg study and 1.00 ng/mL for valacyclovir and 20.00 ng/mL for acyclovir for the 1000 mg study). Pharmacokinetic parameters used for bioequivalence assessment were the area under the concentration-time curve from time zero to time of last non-zero concentration (AUC(0-t)) and from time zero to infinity (AUC(0-inf)) and maximum observed concentration (C-max). These parameters were determined from the valacyclovir concentration data using non-compartmental analysis. In the study with valacyclovir 250 mg formulations, the 90% confidence intervals obtamed by analysis of variance (ANOVA) for valacyclovir were 107.54-124.26% for C-max, 95.45-103.46% for AUC(0-inf) and 95.53-103.63% for AUC(0-t) whereas for acyclovir the 90% confidence intervals obtained were 103.19-117.02% for C-max, 99.61-106.92% for AUC(0-inf) and 99.58-106.94% for AUC(0-t) In the study with valacyclovir 1000 mg formulations, the 90% confidence intervals obtained for valacyclovir were 93.20-107.35% for C-max, 90.87-96.27% for AUC(0-inf) and 90.87-96.27% for AUC(0-t) whereas for acyclovir the 90% CIs obtained were 95.98-104.94% for C-max, 97.13-103.94% for AUC(0-inf) and 97.14-104.09% for AUC(0-t). All the 90% confidence intervals obtained for all the parameters assessed were within the predefined range (80-125%). Based on these results, it can be concluded that the evaluated formulations are bioequivalent in terms of rate and extent of absorption.