Population Pharmacokinetics And Clinical Prognosis Of Metoprolol Succinate Sustained-release Tablets In Patients With Acute Coronary Syndrome After Coronary Intervention

Purposes:Establishment of a population pharmacokinetics(PPK)model of metoprolol succinate sustainedrelease tablets(MET)in patients with acute coronary syndrome after coronary intervention for individualized recommendation of MET initial dose.Methods:1.120 patients with acute coronary syndrome after PCI were recruited as the modeling group,Blood samples were collected and patient clinical data were recorded.Additional 22 patient blood samples and clinical data were collected as external validation groups.2.Gene polymorphisms in CYP2D6*10(100 C>T)and ADRB1(1165G>C)were detected by gene microarray analysis.3.Metoprolol concentration in human plasma was quantitative determinated by highperformance liquid chromatograpby-tandem mass spectrometry(HPLC-MS).4.The nonlinear mixed effect model(NONMEM)method was used to investigate the effects of physiological factors,pathological conditions,genetic factors,and concomitant medication on the pharmacokinetic parameters of MET,and the simplest and final models were established.The prediction performance of the model was evaluated by comparing the predicted value and the actual detected value of the model;The stability of the model was evaluated by the non-parametric bootstrap method;the NPDE(normalized prediction distribution errors)test method was used to investigate the internal prediction ability of the model.The external prediction performance of the model was examined by comparing the MPE%(mean prediction error)and MAE%(mean absolute prediction error)ofthe simplest model and the final model to the external validation group.5.Based on the final model,Monte Carlo method was used to detemine the recommended MET dose for PCI patients with acute coronary syndromes.6.300 patients with acute coronary syndrome after PCI were randomly divided into a titration group and a recommended group to verify the efficacy and safety of the recommended dose.Results:1.The distribution frequencies of CYP2D6,ADRB1 genotypes and allele distribution in 120 ACS patients after PCI were in accordance with the Hardy-Weinberg equilibrium law.2.Regression equation of metoprolol concentration determined by HPLC-MS was Y=0.0294X-0.0022(r=0.9995,n=8).The detection limit is 0.16ng/ml The recovery,precision and stability oft he method meet the detection requirements.3.The final PPKmodel for MET is:CL/F(L/h)=θCL ×θCYP ×θATO × eηCL(IF ATO=0,OATO=1;IF ATO=1,OATO=1.53;IF Genotype of CYP=1,θCYP=1;Genotype of CYP=2,θCYP2=θCYP2=0.686;if Genotype of CYP=3,θCYP=θCYP3=0.284)V/F(L)=8680Compared with wild type(CYP2D6*10 CC),the clearance rate of CYP2D6*10 CT genotype carriers decreased by 31 4%,and the clearance rate of CYP2D6*10 TT genotype carriers decreased by 71.6%.Combined use of atorvastatin increased the clearance of metoprolol by 53%.4.The fitting degree of th model diagnostic chart of the final model is better than the simplest model;the non-parametric bootstrap(Bootstrap)method verifies that the model has good stability;the homogeneity of NPDE variance obeys the normal distribution,and the internal verification shows the prediction performance and model repressentativeness good.The final model has good predictive ability on external data and is better than the simplest model.5.To develop the recommended initial dosage scale for metoprolol succinate sustained-release tablets in patients with acute coronary syndrome after PCI.6.The recommended dose has been clinically verified,and the reresting heart rate compliance rate in the recommended group at 2 weeks was significantly higher than that in the titration group(86.1%vs 59.1%),and the time for reaching the target resting heart rate was significantly shorten(19.26±6.52 days vs 29.32±10.81 days),and the incidence of fatigue,hypotension(systolic blood pressure<100mmHg),and bradycardia(resting heart rate less than 50 beats/min)was significantly lower than titration Group.Conclusion:The PPK model of MET in patients with acute coronary syndrome after PCI established in this study is stable,effective,and has strong predictive ability,and can accurately estimate individual CL;The model can be used to infer the individualized dose of MET,and the clinical validation effect is good.