Analysis of statistical parameters used in bioequivalence assessment of a novel generic anthelmintic formula for sheep

Abstract

Bioequivalence testing is one of the essential procedures used for marketing authorisation of veterinary medicinal products.The aim of this study was to implement a minimum set of statistical parameters in the bioequivalence assessment protocol of two anthelmintic formulas based on Triclabendazole (50 mg/mL) and Ivermectin (1 mg /mL), orally administered to sheep. The study can be synthesized to determine the relative bioavailability and bioequivalence of the two products on 36 clinically healthy sheep, following an unicentric, randomized, cross-over, two-sequence, two-treatment and 14-day wash-out study design. Determination of plasma concentrations of Triclabendazole sulfoxide and Ivermectin was made by two rapid, selective high performance liquid chromatography coupled with mass spectrometry (LC-MS/MS) methods. According to the implemented protocol, the statistical analysis of the data obtained corroborated a set of descriptive parameters (mean, standard deviation, interval) for the sample of subjects (age, weight) with pharmacokinetic parameters relevant for the active substances (Cmax, AUClast, AUCtot) with additional parameters (% extrapolated AUC, thalf, MRT) and drug safety (adverse events, clinical and laboratory screening and follow-up examinations). For bioequivalence assessment to all the primary pharmacokinetic parameters considered (Cmax, AUClast), a confidence interval of 90% for the ratio of the population means must be calculated. All these pharmacokinetic parameters were planned for analysis using ANOVA, after the data have been transformed (logarithmic transformation). A reference 90% confidence interval of 0.8 – 1.25 was chosen. The bioequivalence can be concluded if the calculated 90% confidence interval around the ratio of means (Test/Reference) using log transformed data falls within the reference acceptance range of 0.8–1.25 for all primary pharmacokinetic parameters of triclabendazole sulfoxide and ivermectin. Finally, the bioequivalence of the two anthelmintic products and, respectively, the possibility of exchanging information between them in the veterinary therapeutic field is determined on the basis of the relevance of the values obtained in the statistical analyzes, especially of the pharmacokinetic parameters.