Study On Bioequivalence Assessment Of Metformin Hydrochloride By Limited Sampling Strategy

Objective To develop limited sampling strategy (LSS) for estimating metformin hydrochloride bioequivalence parameters Cmax and AUC0-24. To calculate the pharmacokineties of metformin hydrochloride tablets in Chinese healthy volunteers. To evaluate the bioequivalence of metformin hydrochloride reference and test in a randomized cross over and two period design trial. And assess the bioequivalence of metformin hydrochloride by LSS model.Methods Twenty male healthy subjects enrolled in a bioequivalence study, All subjects were divided randomly two groups and administered orally reference and test formulation of 1000mg metformin hydrochloride. The blood concentrations of metformin hydrochloride were determined by the validated HPLC method. A multiple linear regression analysis was developed for estimating AUC0-24 using the metformin hydrochloride concentration of the reference formulation to develop LSS models. The LSS models were internally validated by the Jackknife method. The models were also externally validated by test formulation and simulated sets generated by Monte-Carlo simulation.Bioequivalence assessment of the metformin hydrochloride, based on LSS derived Cmax and AUC0-24 values, was identified to those obtained using traditional method.Results1. The results of bioequivalence assessment by classic method.After taking the test and the reference, the Cmax were:2034.89±640.36ng/ml and 2232.13±605.89ng/ml. The Tmax were:1.88±0.60h and 1.70±0.52h. The AUC0-24 were 11367.84±3164.48(ng/ml)h and 11352.10±2609.48(ng/ml)h. All parameters were no significant difference (P>0.05). The bioavailability were 100.42±15.05%.2. The results of bioequivalence assessment by LSS. The linearity relationship between the parameters and single concentration point was poor. Several models for these parameters estimation met the predefined criteria (r2>0.94). Validation tests indicated that most informative sampling points C1, C1.5, C2, C4, C10 provided accurate estimations of these parameters-AUC0-24, Cmax. The Cmax were: 2052.25±662.90ng/ml and 2216.71±582.67ng/ml. The AUC(0-24) were 11441.37±3333.41(ng/ml)h and 11379.84±2571.67(ng/ml)h. All parameters were no significant difference (P>0.05). The bioavailability was 100.15±12.20%.Conclusion The bioequivalence assessment results showed that LSS models provided correct assessment of bioequivalence between two metformin hydrochloride preparations. The method is accurant and can be considered desirable for metformin hydrochloride bioequivalence study.