Pharmacokinetics

The aim of this study was to evaluate the bioequivalence of Diopolol (containing Bisoprolol fumarate 10 mg) tablet of SAVA Healthcare Ltd, India with Concore (Containing Bisoprolol hemifumarate 10 mg) tablet of Merck Serono, Germany in healthy adult volunteers. This open label, balanced, single-dose, randomized, two period, two sequences ,crossover oral bioequivalence study was conducted in 24 healthy human adult male subjects under fasting condition. Subjects received bisoprolol 10 mg of either test or reference formulation with a washout period of 7 days. After study drug administration, serial blood samples were collected over a period of 48 hours. The plasma concentrations of bisoprolol were determined by a validated method using LC/MS/MS. Pharmacokinetic parameters Cmax, Tmax, T1/2, AUC0-t, AUC0-∞, and kel, were determined for both the formulations. The formulations were to be considered bioequivalent if the geometric least square mean ratio of test and reference of Cmax, AUC0-t, and AUC0-∞, were within the predetermined bioequivalence range of 80% to 125%. A total of 24 subjects were enrolled. No significant differences were found based on analysis of variance. The 90% confidence intervals (CI) of Cmax, AUC0-t and AUC0-∞, of bisoprolol were 103.29 - 115.15, 103.73 - 116.62, and 94.78 - 116.64 respectively This study shows that the test formulation is bioequivalent to the reference formulation for bisoprolol.

The present study was aimed to study the requirements of bioequivalence for registration of pharmaceutical products in various countries. It is essential for pharmaceutical industry to study the guidelines of bioequivalence for respective country where industry would like to apply for ANDA and thus want to enter into generic market. This study gives insight about requirements of bioequivalence with study parameters such as study design, fasting or fed state studies, volunteers recruitment, study dose, sampling points, analytical method validation parameters, moieties to be measured in plasma, pharmacokinetic parameters, criteria for bioequivalence, GCP requirements etc. which are needed for pharmaceutical industry to carry out bioequivalence studies and to file ANDA. Test products for these bioequivalence studies are usually manufactured by a sponsor or manufacturer while reference is provided by the government laboratories of respective countries. Sampling points also varies with respect to the regulatory guidelines of these countries. India follows Indian GCP guidelines, South-Africa MCC GCP guidelines and Australia follows ICH GCP guidelines. Criteria of bioequivalence, for India and South-Africa is 90% CI 80-125% for Cmax, AUCt, AUCo-inf. for Australia 90% CI 80-125% for Cmax, hAUCt, AUCo-inf.