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.
Medical Department, Grupo Tecnimede, Sintra, Portugal. dmed.ct@tecnimede.pt
Rita
R
Neves
Susana
S
Almeida
Augusto
A
Filipe
Ana Cristina Franco
AC
Spinola
Zohreh
Z
Abolfathi
Ann
A
Lévesque
Jordi
J
Ortuño
Alex
A
Torns
D000212:Acyclovir / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012015:Reference Standards; D013608:Tablets, Enteric-Coated; D013810:Therapeutic Equivalency; D000077483:Valacyclovir; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D055815:Young Adult
D000998:Antiviral Agents; D013608:Tablets, Enteric-Coated; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir