Pharmacokinetics And Pharmacodynamics Equivalence Study On Brand-name And Generic Metformin Tablets

Many generics of metformin were available and applied widely in type 2 diabetes mellitus in China.CFDA had announced the " opinions of General Office of the State Council for developing the evaluation of quality and efficacy consistency of generics"in 2015,indicated that generics must pass the dissolution test and bioequivalence test for approval of generics.Whether generics are bioequivalent and clinical equivalent with the brand-name is still a vital problem for both physicians and patients.The study compare the consistency between the generic and brand-name metformin through dissolution/release rate test in vitro and bioequivalence and clinical equivalence in vivo tests.Objective:This study aimed to explore the consistency with the brand-name in the behavior of dissolution/release,bioequivalence and clinical efficacy by appearance and the dissolution/release rate test in vitro and pharmacokinetics and pharmacodynamics test in vivo,so that suggest physicians and patients choosing the better drugs.Methods:In this study,three kinds of common and sustained released metformin tablets were selected to compare with the brand-name drug in appearance,dissolution/release behavior in vitro respectively and one of those was chosen to finish the pharmacokinetics and pharmacodynamics test in vivo.In dissolution/release test,the dissolution/release rate of different drugs were determined by basket method.,and the dissolution/release consistency was proved by comparing dissolution/release parameters and f2 values of the curve.The common one behaved the most different from the brand-name drug was selected for the bioequivalence and pharmacodynamic test in ZDF(Zucker Diabetes Fatty)rats,a diabetes animal model.The bioequivalence of generic and brand-name drug was performed by comparing the F values of ABE(Average Bioequivalence)analyze and pharmacokinetic parameters according to the drug concentration-time curve of the ZDF rats,which were given the same dose(180 mg·kg-1·d-1)of the brand-name and generic metformin.In the pharmacodynamic test,clinical equivalence of generic and brand-name drug was verified through comparing relevant clinical indicators,blood glucose and blood lipid,insulin and HOMA-IR,of rats given different oral doses in once or long-term(6 weeks).Results:? Appearance:In the study of 46 varieties of tablets,there are 4 varieties of drugs in appearance shape does not meet the criterion of the Chinese Pharmacopoeia(2015).? Dissolution/release studies:two generic common metformin tablets behaved significant different with brand-name common drug(with f2 values of 42.38%,49.30%and 62.2%,respectively)and three generic sustained-release metformin tablets was similar to that of the brand-name(with f2 values of 54.95,55.17%and 67.42%,respectively).? Bioequivalence study:The chosen generic for in vivo test failed to show similar pharmacokinetic characteristics and treatment effects in diabetes rats compared with brand-name drug.Bioavailability F of AUC0-t,AUC0-?,Cmax equivalence analyse for ABE(Average Bioequivalence)were 138.6%,116.2%and 128.7%,respectively.? Pharmacodynamic study:Generic metformin(300 mg/kg-d)decreased more fasting blood glucose of ZDF rats for 5.9±4.07mmol/L,GSP for 0.09±0.26 mmol/L,weight for 11.83±6.87 g and blood insulin for 0.56±1.18 ?g/L than brand-name one(300 mg/kg·d).In addition,the brand-name drug was more effective to improve HDL-C compared with generic drug.Although generic drug had more drug exposure than brand-name one,hypoglycemic effect didn't show better.Conclusions:Generics showed a certain gap with brand-name in both in vitro and in vivo researches,and consistency evaluation of generic drugs should be in accordance with both bioequivalence and clinical equivalence results.