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 postdose 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 tained 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.

Two-way crossover bioequivalence study of alendronate sodium tablets in healthy, non-smoking male volunteers under fasted conditions.

This study was conducted in order to assess the bioequivalence of two different formulations containing 70 mg alendronate sodium (CAS 121268-17-5) under fasted conditions. One hundred twenty-two healthy male volunteers were enrolled in an open label, randomized, crossover design with a wash-out period of 20 days in one study center. Urine samples were collected up to 36 h post-dose, and the concentrations of alendronic acid were determined using a high performance liquid chromatographic method with pre-derivatization and fluorescence detection (HPLC/FL) method. The mean Ae(0-t) were 604.24 +/- 348.73 microg and 627.36 +/- 327.99 microg, while the mean R(max) were 193.87 +/- 114.68 microg/h and 202.00 +/- 107.83 microg/h for the test and reference formulations, respectively. The T(max) of the test and reference tablets were 1.26 +/- 0.58 h and 1.26 +/- 0.51 h, respectively. No significant differences of pharmacokinetic parameters between the two studied formulations were found. The 90% confidence intervals for the primary target parameters, intra-individual ratios for Ae(0-t) and R(max) of alendronic acid, were between 0.86-1.00 and 0.85-1.01, respectively, and thus within the acceptance range for bioequivalence criteria. In the light of the present study it can be concluded that the test formulation is bioequivalent to the reference formulation.

Bioequivalence study of two different film-coated tablet formulations of losartan-hydrochlorothiazide in healthy volunteers.

The study was conducted in order to assess the bioequivalence of two film-coated formulations containing 100 mg of losartan (CAS 124750-99-8) and 12.5 mg of hydrochlorothiazide (CAS 58-93-5). Seventy-three healthy subjects were enrolled in a randomised, single-dose, open-label, two-way crossover study, with a minimum washout period of 7 days. A total of 21 blood samples were collected up to 36 h post-dosing. Losartan, losartan carboxy acid and hydrochlorothiazide levels were determined by liquid chromatography with tandem mass detection (lower limit of quantification: 1.01 ng/mL for hydrochlorothiazide, 2.02 ng/mL for losartan and 2.51 ng/mL for losartan carboxy acid). Pharmacokinetic parameters used for bioequivalence assessment (AUC(0-t) and Cmax as primary and AUC(0-inf) as secondary pharmacokinetic parameters) were determined from the losartan and hydrochlorothiazide concentration data using non-compartmental analysis. Data from losartan carboxy acid was reported and presented as supportive data. The 90% confidence intervals (obtained by ANOVA) for losartan were 97.05-118.48% for Cmax 100.76-106.10% for AUC(0-t) and 100.80-106.10% for AUC(0-inf) whereas for hydrochlorothiazide the 90% confidence intervals obtained were 103.94-115.33% for Cmax, 101.97-109.61% for AUC(0-t) and 101.77-109.02% for AUC(0-inf), and for losartan carboxy acid the intervals obtained were 98.31-107.82% for Cmax, 97.89-104.30% for AUC(0-t) and 98.06-104.30% for AUC(0-inf). All the 90% confidence intervals obtained for all the parameters assessed were within the predefined ranges (80-125%). Based on these results, it can be concluded that the evaluated formulations are bioequivalent in terms of rate and extent of absorption.

A pilot study to evaluate the pharmacokinetics of sibutramine in healthy subjects under fasting and fed conditions.

PURPOSE: The purpose of this study was to characterize the food effect on the pharmacokinetics of sibutramine and its pharmacologically active metabolites. METHODS: This was an open label, single dose, crossover study completed by six healthy males. A single dose of sibutramine 15 mg was administered orally under fasting and fed conditions. Plasma concentrations of sibutramine and its metabolites were determined by LC/MS/MS: Non-compartmental pharmacokinetics and statistical analysis were performed using SAS. RESULTS: The food intake increased significantly AUCs and C(max) of sibutramine and its M1 metabolite, but did not affect M2 metabolite. When sibutramine was administered with food, the T(max) was delayed by 2 to 4 hours for sibutramine, M1 and M2 metabolites as stated in the literature. CONCLUSIONS: The results of this study indicate that sibutramine is measurable using a sensitive bioanalytical method. In contrast with what is reported in the product monograph, this study demonstrated that the bioavailability of sibutramine and M1 metabolite was significantly increased with administration with food. The results confirmed lack of food effect on the pharmacokinetics of M2 metabolite. These relatively large food effect observed for sibutramine and M1 metabolite, could have implication for the efficacy and safety of the drug.