The Drug Monitoring Study Of Atorvastatin And Rosuvastatin

ObjectiveAtorvastatin and rosuvastatin are most commonly used statin lipid-lowering drugs in clinical practice.Their clinical applications include difficulties in selecting the treatment intensity,and the main efficacy index of low-density lipoprotein cholesterol(LDL-C)has a low compliance rate.Problems that increase the risk of cardiovascular events and adverse reactions in clinical patients Therapeutic drug monitoring takes blood drug concentration monitoring as the core,combined with pharmacokinetic data,to provide a basis for individualized clinical medication.Use therapeutic drug monitoring on patients can significantly improve the efficacy of drugs and reduce the risk of adverse reactions.Therefore,this study established a monitoring method for simultaneous determination of rosuvastatin,atorvastatin and its main metabolite blood concentration,to providing an experimental basis for the monitoring of statins.In this study,a physiologically based pharmacokinetics(PBPK)model was used to established the PBPK model of atorvastatin,provides the basis pharmacokinetics result for therapeutic drug monitoring.On the basis of establishing and verifying the blood concentration monitoring method of statins and the PBPK model,the patients use statins be for initial therapeutic drug monitoring in order to improve the safety and effectiveness of lipid-lowering therapy and provide a basis of personalized lipid-lowering therapy.MethodsEstablished method determination of rosuvastatin,atorvastatin and its main metabolites at same time.Establishment and verification atorvastatin PBPK model and using PBPK model to study the drug-drug interaction.Start first-step therapeutic drug monitoring for clinal patient.(1)Using UPLC-MS/MS technology to establish a method for the monitoring of rosuvastatin,atorvastatin and the main metabolites 2-hydroxyatorvastatin,4-hydroxyatorvastatin,atorvastatin lactone in the plasma samples of patients which provide an experimental basis for the therapeutic drug monitoring of statins.(2)On the GastroPlusTM software platform,using the corrected physical and chemical parameters and in vitro enzymatic kinetic parameters to establish the PBPK model of atorvastatin in healthy adult volunteers,to simulate the drug-time curve of atorvastatin in vivo,to obtain the pharmacokinetic parameters and verify the model.A DDI model of atorvastatin and a typical CYP3A4 inhibitor was established and validated.The validated model was used to predict the DDIs of atorvastatin combined with CYP3 A4 inhibitor in Chinese population.(3)Use established statin blood concentration measurement methods to monitor the blood concentration of clinical patients,obtain the blood concentration and time information of clinical patients using statins,and use the established atorvastatin PBPK model to simulate the drug-time of vastatin in elderly clinical patients.Use the patient's SNPs information to group patients,and verify the degree of fitting of the established PBPK model to the predictive value of blood concentration of patients with different polymorphisms,and carry out preliminary treatment drugs for patients using statins monitoring research.Results(1)Established a UPLC-MS/MS method for simultaneous monitoring of rosuvastatin,atorvastatin,2-hydroxyatorvastatin,4-hydroxyatorvastatin,atorvastatin lactone in patients'plasma samples.The linear range of RT was 0.1-50 ng/ml.The linear regression equation was good(r2=0.9977),T he linear regression equation for AT,ATL,O-AT and P-AT was 0.05-50 ng/ml.The linear regression equations were good(r2=0.9997?0.9988?0.9923?0.9995),the lower limit of quantification of RT is 0.1 ng/ml,and the lower limit of quantification of AT,ATL,OAT and P-AT is 0.05 ng/ml.The intra-day and inter-day precision(RSD)of the five analytes are less than 15%,and the accuracy is between-10.0%and 6.1%.The recovery rates of the five analytes are between 75%and 108%.Matrix effect of variation RSD<15%,the stability of the test object was investigated under different conditions(24 hours at 25? 24 hours at 4?,3 freeze-thaw cycles,30 days at-80?,under the temperature of the injector 24 hours),except that part of the atorvastatin lactone is hydrolyzed at room temperature(25?)for 24 hours,the rest of the test substance has good stability.(2)On the GastroPlusTM software platform,established the PBPK basic model of atorvastatin in healthy adult volunteers,and established,set up and verified the DDI model of atorvastatin with typical CYP3A4 inhibitors.The predicted values of atorvastatin's Cmax,AUC(0-72h),AUC(0-inf)by models with real values Between 0.93 and 1.07 times.Predict the pharmacokinetic parameters of atorvastatin combined with itraconazole,the predicted value of the atorvastatin Cmax,AUC(0-72h),AUC(0-inf)by model of the true value is Between 0.67?1.87 times,the DDI model was used to predict the changes of atorvastatin pharmacokinetics when atorvastatin Combined with CYP3A4 inhibitor in the Chinese population.The combination of atorvastatin and itraconazole will increase the Cmax,AUC(0-72h)and AUC(0-inf)of atorvastatin double times and the combination with voriconazole will make atorvastatin Its Cmax,AUC(0-72h),AUC(0-inf)increased by 20%,but voriconazole as non-competitive CYP3A4 inhibition will significantly increase the effect of voriconazole on atorvastatin exposure during multi-dose treatment.(3)Monitored blood concentration of clinical patients with established statin blood concentration measurement methods.Obtain blood concentration and time information of clinical patients using statins The PBPK model of atorvastatin was used to extrapolate to establish the PBPK model of atorvastatin in the elderly clinical patient population.Combined with the patient's physiology,pathology and medication information for preliminary treatment drug monitoring research.The treatment drug monitoring study of 18 patients using atorvastatin showed that the established PBPK model can better predict the blood concentration of atorvastatin at the time of blood collection,and the blood concentration of 15 patients was at the predicted value 0.5?2.0 times nearby.The blood drug concentration data of 3 patients exceeded the range,and the medical record information may be related to the patient's SLCO1B1 polymorphism and combined medication.Blood concentration monitoring of clinical patients using rosuvastatin shows that gene polymorphism of SLCO1B1 521TC patients with rosuvastatin blood concentration higher than gene polymorphism of SLCO1B1 521TT patients,studies show SLCO1B1 521T>C mutation will significantly increase the amount of rosuvastatin exposure in patients,which is consistent with the results of pharmacokinetics study.Conclusion(1)This study establish a UPLC-MS/MS method for the simultaneous determination of blood concentrations of atorvastatin,rosuvastatin and its main metabolites in clinical patients.The method validation results showed the specificity,linearity,Precision,accuracy,recovery rate,matrix effect,etc.all meet the requirements of the guidline principles.The established method is simple,stable and reliable,and can be used to monitor the blood concentration of clinical patients.(2)Establish and verify the PBPK model and DDI model of atorvastatin,study the pharmacokinetics and drug interactions of atorvastatin in the Chinese population,atorvastatin combined with a typical CYP4A4 inhibitor(Itraconazole,voriconazole)can significantly increase the exposure of atorvastatin in the Chinese population and increase the risk of adverse reactions in patients.Therefore,when atorvastatin is used in combination with CYP4A4 inhibitors,the dosage should be adjusted appropriately to improve the safety and effectiveness of lipid-lowering therapy.(3)The established blood drug concentration determination method and PBPK model were used to conduct a preliminary therapeutic drug monitoring study for clinical patients using statins.The PBPK model can better predict the blood concentration of statins at the blood collection time of clinical patients using atorvastatin lipid-lowering therapy,and can predict the exposure of atorvastatin in patients.Combined with the patient's genetic polymorphism information and combined medication information,a preliminary therapeutic drug monitoring study was carried out,which can provide a basis for the clinical adjustment dose of statins.