Pharmacokinetics And Bioequivalence Study Of Trimetazidine Sustained-Release Tablets In Humans

Background:Trimetazidine is mainly used in the symptomatic treatment of adult patients with poorly controlled or intolerable stable angina pectoris.In 2000,trimetazidine was imported for the first time in China,and then a number of generic drugs has appeared on the market.Carrying out the consistency evaluation of trimetazidine generic drugs to ensure the quality of generic drugs can improve the safety and effectiveness of generic drugs and ensure the safety of people’s medication.At present,most of the published studies on the bioequivalence（Bioequivalency,BE）of trimetazidine were conducted in men on an empty stomach,without examining the effects of gender and high-fat diet on the results of the trial.It is necessary to conduct a BE study on oral trimetazidine sustained-release tablets in Chinese healthy subjects under fasting and fed conditionsin accordance with the current guiding principles of bioequivalence tests.At the same time,the effects of gender and dietary status on the pharmacokinetics and bioavailability of trimetazidine were investigated,and their in vitro and in vivo correlations were established to provide a theoretical basis for the drug safety and clinical rational drug use of trimetazidine sustained-release tablets.Objective:This study aims to evaluate the bioavailability and bioequivalence of domestic generic trimetazidine sustained-release tablets and original reference tablets in healthy volunteers and to investigate the pharmacokinetic differences of trimetazidine sustained-release tablets after oral administration of trimetazidine sustained-release tablets on the fast and fed state.At the same time,gender differences in the pharmacokinetic parameters and the correlation between in vivo absorption and in vitro release of trimetazidine sustained-release tablets were studied.Methods:（1）The concentration of trimetazidine in human plasma was determined by ultra high performance liquid chromatography-electrospray tandem mass spectrometry.（2）The trial was designed as a single-center,randomized,open-label,4-period crossover bioequivelence study.A total of 24 eligible healthy subjects were enrolled in the study.Venous blood was taken at the designed time to determine the plasma concentration of trimetazidine in the subjects.The main pharmacokinetic parameters were calculated,and the bioequivalence was determined by multivariate analysis of variance,t-test and 90%confidence interval method（CI）.T-test was used to investigate the effect of high-fat diet on the pharmacokinetics of trimetazidine and whether there were gender differences in pharmacokinetic parameters.（3）The compartmentmodel dependence method and Loo-Riegelman method were used to calculate the percentage of drug absorption in vivo,and the correlation in vivo and in vitro was established.Results:（1）The UPLC-MS/MS method established in this study is simple,rapid and sensitive,which can be used to study the bioequivalence and pharmacokinetics of trimetazidine.（2）All 24 subjects completed the whole trial.According to the analysis of variance,there was no significant difference in the principal pharmacokinetic parameters between the Test preparation（T）and the Reference preparation（R）.The 90%CI of ln AUC_0-36,ln AUC_0-∞and ln C_maxin fasting state were 98.38%-104.90%,98.13%-104.95%and 101.45%-112.23%,respectively,and ln AUC_0-36,ln AUC_0-∞and ln C_max 90%CI in fed state were 96.38%-101.52%,96.37%-101.64%and 93.88%-102.58%,respectively,which were all within the range of 80.00%-125.00%.And the results of double one-sided t-test were P<0.05.The relative bioavailability of T drug to R drug on fasting and fed state was 100.25±1.32%and 99.85±1.09%,respectively.The pharmacokinetic parameters of trimetazidine sustained-release tablets were analyzed and compared in healthy volunteers.The results of t-test showed that there was no difference in t_max,AUC_0-36,AUC_0-∞and t_1/2（P>0.05）.C_maxwas 73.72±13.10 ng/m L in fasting state and C_max was 81.95±13.07 ng/m L in fed state（P<0.05）.The pharmacokinetic parameters of trimetazidine sustained release tablets in male and female subjects were compared.The results showed that there were gender differences in the main pharmacokinetic parameters.AUC and C_maxwere higher in females than in males,and Vd and CL in males were higher than those in females,but there was no significant difference in t_max and t_1/2.（3）The absorption percentage(F_abs)of trimetazidine sustained-release reference preparation and the cumulative release rate(F_diss)in vitro at the corresponding time points in the media of p H1.2,p H4.5 and p H6.8 were regressed to establish IVIVC,and the regression equations were obtained as follows:F_abs=1.174F_diss-8.412,r=0.9881;F_abs=1.245F_diss-16.27,r=0.9957;F_abs=1.249F_diss-15.48,r=0.9950.The test preparation F_abs of trimetazidine sustained-release tablets and F_dissat each corresponding time point in p H1.2,p H4.5,p H6.8 media were regressed to establish IVIVC,and the regression equations were obtained as follows:F_abs=1.323F_diss-25.00,r=0.9982;F_abs=1.359F_diss-28.12,r=0.9983;F_abs=1.353F_diss-28.91,r=0.9987.The correlation coefficient r of trimetazidine sustained release tablets in vivo and in vitro is greater than the critical value of the degree of freedom P=0.001:r（4,0.001）=0.9741.Conclusion:（1）The established UPLC-MS/MS analysis method is simple,accurate,reliable,sensitive and suitable for the study of pharmacokinetics and bioequivalence of trimetazidine.（2）The trial preparation and reference preparation of trimetazidine sustained-release tablets are bioequivalent.In Chinese healthy subjects,except for a slight higher C_max in fed state,the high-fat diet did not affect the absorption of trimetazidine in vivo.There may be gender differences in the pharmacokinetic parameters of trimetazidine sustained-release tablets,which need to be further verified by expanding the sample size.（3）There was a good correlation between the absorption percentage in vivo and the cumulative release in vitro of trimetazidine sustained-release tablets in p H1.2,p H4.5 and p H6.8.