A Forecasting Study On The Pharmacokinetics Of Metofazone,valsartan And In Patients With Renal Injuries And Effect Of Diet On Pravastatin Calcium Tablet

BackgroundIn the process of drug clinical application,adverse drug reaction usually happens due to drugs interaction.Serious adverse drug reactions can lead to damage to the body of the patient,and even drug withdrawal.Only within the scope of China,there are 30%of the total population of taking medicine are affected by adverse reaction caused by drug interaction.Some serious drug interactions even lead to death.The safety and effectiveness of medications have been weakend by drug reactions seriously.The interaction between drugs can be split according to the interaction of physical and chemical properties,interaction of pharmacokinetic and interaction of pharmacodynamic.In order to improve the safety,and efficacy of medcine using,the study of establishing scientific and accurate drug interactions in vivo prediction research method will play a positive role in the management and control of clinical risk of drugs.This research foucued on the FDA-recommended combination drug regimen,metolazone and valsartan combination treatment,research on the process of pharmacokinetics reaction based on the PBPK model.Through the DDI ratio between these two drugs,wether the interaction will be induced by the drug combination,so as to induced adverse reaction.Besides that,drug interaction research also included the effect of food to drug,we combined the research of the effect of PBPK model on the diet of pitavastatin calcium on the basis of body pharmacokinetics experiment of pitavastatin calcium when fasting and postprandial condition.The diet effect is determined by the AUC ratio before and after meal,and the accuracy of model predictions are determined by fold-error value.Objective1.Pharmacokinetic properties of single-and multiple-dose metolazone tablets in healthy Chinese volunteers;Building the fundamental PBPK model of metolazone and valsartan.2.PBPK model combined with CYP2C9 enzyme activity inhibits method to observe the drug combination of metolazone and valsartan to the renal damage patients.3.Prediction and study of the fasting and postprandial pharmacokinetic parameters of pravastatin based on PBPK model combined with pharmacokinetics is studied.Methods1.Pharmacokinetic properties of single and multiple-dose metolazone tablets in healthy Chinese volunteers.The study enrolled 30?15 male and 15 female?healthy Chinese volunteers.Based on a computer-generated table of random numbers,30 subjects were allocated in a 1:1:1 ratio to receive a single 0.5 mg,1 mg,or 2 mg metolazone tablet in randomized sequence.This study was designed as an open-label,randomized,single center,single dose and multiple dose pharmacokinetic study that included 3 study groups.Sensitive and simple LC-MS/MS methods for quantitative determination of metolazone in human plasma were developed.2.Building the fundamental PBPK model of metolazone and valsartan.Collect parameters related with two drugs.Examine the resource of each parameter to establish model.In the PK prediction module of input PBPK model software,model operation,construct,optimization;the PK parameters and curve obtained in PBPK model prediction is compared with measured data.The rationality of each parameter and the choice of formula was re-checked.And the pharmacokinetic parameter obtained simulates in final established drug PBPK model is compared with test measured or the data reported in publications.Model prediction and measured curve fitting?R²?are used to predict the measured curve fitting error?RMSE?and the accuracy of the established model verified by predict error?PE?.3.Prediction and study on the pharmacokinetics of valsartan and metolazone in renal damage patients based on PBPK model.On the basis of the model theory of competitive inhibition and PBPK model software,valsartan is used as the metabolism substrate of P4502C9 enzyme,metolazone is used as the inhibitor of P4502C9 enzyme,and the DDI module of PBPK model software was used to predict by using the DDI ratio value to determine the potential effects of matolazone to the PK curve of valsartan.4.The research of the inhibited function of metolazone on CYP2C9 enzyme activity.The metabolite production quantity of the CYP2C9 enzyme substrate reflected the enzyme.When the enzyme activity is inhibited to 50%,the concentration of metolazone is IC50 which is used to observe the inhibitory of metolazone to CYP2C9 enzyme.5.Pharmacokinetic Properties of pravastatin in healthy Chinese volunteers.24 volunteers?12 male and 12 female?were enrolled in the study.Subjects were allocated in a 1:1 ratio to receive a single 2 mg pravastatin calcium tablet in randomized sequence.Sensitive and simple LC-MS/MS methods for quantitative determination of pravastatin in human plasma were developed.6.Prediction and study of the fasting and postprandial pharmacokinetic parameters of pravastatin based on PBPK model.Collect parameters related with pravastatin.Examine the resource of each parameter to establish model.In the PK prediction module of input PBPK model software,model operation,construct,optimization;the PK parameters and curve obtained in PBPK model prediction is compared with measured data.The rationality of each parameter and the choice of formula was re-checked.And the pharmacokinetic parameter obtained simulates in final established drug PBPK model is compared with test measured or the data reported in publications.The accuracy of the established model was verified by Fold-error.Results1.Pharmacokinetic parameters of metolazone.1.1 Pharmacokinetic parameters of single and multiple dosing of metolazone:The pharmacokinetic parameters of0.5 mg group?Mean±SD,Day 1?:Kel:0.1002±0.0309 1/h,t_1/2:7.47±2.06 h,C_max:8.2252±2.7712 ng/mL,t_max:1.63±0.46 h,AUC_0-t:49.68±14.16 ng·h/mL,AUC_0-?:50.51±14.60 ng·h/mL,Vd:108732±21357mL,CL:10645.1±3021.0 mL/h,MRT_0-t:8.73±3.49 h,MRT_0-?:9.43±3.63 h;The pharmacokinetic parameters of 0.5 mg group?Mean±SD,Day 9?:Kel:0.0957±0.0227 1/h,t_1/2:7.61±1.76 h,C_max:8.1967±2.0941 ng/mL,t_max:1.63±0.41 h,AUC_0-t:51.35±15.02 ng·h/mL,AUC_0-?:52.26±15.28 ng·h/mL,C_min:0.3962±0.2258 ng/mL,C_avg:1.9595±0.5118 ng/mL,DF:415.6±143.3%,CL:11267.2±2770.6 mL/h,MRT_0-?:8.97±1.94 h,Vd:122125±38729 mL,AUC_ss:47.03±12.28 ng·h/mL,Accumulation:1.13±0.07,DF/?:17.3±6.0.The pharmacokinetic parameters of 1.0 mg group?Mean±SD?:Kel:0.0966±0.0123 1/h,t_1/2:7.28±0.93 h,C_max:13.8666±4.3227 ng/mL,t_max:1.43±0.39 h,AUC_0-t:91.31±30.39 ng·h/mL,AUC_0-?:92.41±31.38 ng·h/mL,Vd:120081±23585 mL,CL:11755.6±3252.2 mL/h,MRT_0-t:8.80±1.50 h,MRT_0-?:9.31±1.77 h;The pharmacokinetic parameters of 1.0 mg group with high fat condition?Mean±SD?:Kel:0.0892±0.0113 1/h,t_1/2:7.86±0.82 h,C_max:11.4826±3.5083 ng/mL,t_max:2.83±1.12 h,AUC_0-t:88.55±27.28 ng·h/mL,AUC_0-?:89.72±27.63 ng·h/mL,Vd:135593±39880 mL,CL:11930.9±3017.5 mL/h,MRT_0-t:9.90±1.32 h,MRT_0-?:10.54±1.48 h.The pharmacokinetic parameters of 2.0 mg group?Mean±SD?:Kel:0.0969±0.0181 1/h,t_1/2:7.42±1.60 h,C_max:28.8775±11.3863 ng/mL,t_max:2.05±1.11 h,AUC_0-t:184.84±52.39 ng·h/mL,AUC_0-?:186.58±52.50 ng·h/mL,Vd:126326±53382 mL,CL:11630.7±3726.0 mL/h,MRT_0-t:8.14±1.26 h,MRT_0-?:8.64±1.68 h.1.2 Comparison of pharmacokinetic parameters of single and multiple dose:Comparison of pharmacokinetic parameters of single and multiple dose:there were no statistically significant difference,such as C_max,AUC_0-t,AUC_0-?,t_1/2,CL,Vd,MRT_0-?,Kel,t_max?Sig.value>0.05?.Comparison of pharmacokinetic parameters of gender:there were no statistically significant difference between 0.5 mg and 1.0 mg group,such as C_max,AUC_0-t,AUC_0-?,t_1/2,CL,Vd,MRT_0-?,Kel,t_max?Sig.value>0.05?.1.3 Comparison of pharmacokinetic parameters of gender in 2.0 mg group:There was statistically significant difference of gender in 2.0 mg group,such as C_max,AUC_0-t,AUC_0-?,CL,Vd,Kel?Sig.value<0.05?.There was no significant difference in the pharmacokinetic parameters of the other pharmacokinetics?Sig.Value>0.05?.Therefore,factor variance analysis was performed on Kel,C_max,auc_0-t,AUC_0-?,Vd and CL of all single dose groups?the dose and gender as the factors,and weight as covariant?.The results showed that there was no statistically significant difference.1.4 Comparison of pharmacokinetic parameters of different dose:Comparison of pharmacokinetic parameters of different dose:The compared results of the pharmacokinetic parameters of three doses between volunteers suggested obvious differences between the groups,indicating that gender did influence the pharmacokinetic characteristics of C_max,AUC_0-t-t and AUC_0-?.There was no obvious difference between the groups in other parameters.1.5 Comparison of pharmacokinetic parameters between groups of food with high fat condition and fasting state:Firstly,comparison of pharmacokinetic parameters between groups of food with high fat condition and fasting state.There was no statistically significant difference between two groups for C_max,AUC_0-t,AUC_0-??Sig.value>0.05?.There was statistically significant difference between two groups for t_max,Vd?Sig.value<0.05?.The other pharmacokinetic parameters were no statistically significant difference?Sig.value>0.05?.The result shows that the food can affect absorption rate of drug,but it does not affect drug exposure level in vivo.2.Building the fundamental PBPK model of metolazone and valsartan.PBPK model fit different doses of valsartan?51.4mg,102.8mg,80 mg?and metolazone?7.5mg,0.5 mg,1.0 mg,2.0 mg?in Chinese to modeled prediction curve and measured curve's degree of fitting?R²?,predicted curve and measured curve fitting error?RMSE?and the prediction error?PE?show that the PK predicted value and measured value of valsartan and metolazone are very near.From predicted curve fitting trend,the predicted curve showed a trend of basic coincidence with measured data,and the established model can reflect the process of changing of valsartan and metolazone in vivo in Chinese.The PBPK model can better reproduce the clinical trial results of the metolazone in Chinese,and the established PBPK model can be used in the description of ADME process of valsartan and metolazone in Chinese.3.Prediction and study on the pharmacokinetics of valsartan and metolazone in renal damage patients based on PBPK model.The results suggest that the pharmacokinetic behavior of the two drugs in the human body is consistent with the PK behavior of the individual drug.The main PK parameter change ratio is 1.It is suggested that these two drugs do not affect the pharmacokinetics of each other,and each component plays a corresponding role in the human body according to their respective pharmacokinetic characteristics.In the study of drug use of renal damage patients,the characteristics of PK changes in patients with renal damage at different stages were studied after the treatment of valsartan and metolazone alone.The expression of different degree of renal injury in the model,combined with the glomerular filtration rate?GFR?and plasma free drug fraction?algorithm?parameters were adjusted correspondingly.The prediction of the model showed that renal injury affected the absorption,distribution,metabolism and excretion process of torr in human body to a certain extent.There was no significant effect on the longitude process of valsartan.4.The result of the research on inhibitory function of metolazone in CYP2C9enzyme activity.In this study,the enzyme activity IC50 in metolazone to CYP2C9 is 11.5%,which indicated that the inhibitory function of metolazone to CYP2C9 is weaker,and in the clinical application,metolazone showed a lower risk in drug interaction when used with the drug metabolized by CYP2C9 enzyme.5.Prediction and study of the fasting and postprandial pharmacokinetic parameters of pravastatin based on PBPK model.The variation tendency of C_max,AUC_0-t-t and t_maxax were calculate successfully.The simulated pharmacokinetic parameters indicating about 17.0%increase in AUC_0-t,on the other hand,the percent increase in C_max?22.0%?,the simulated t_maxax in the fed state was shifted to a mild higher value.The results of prediction were approaching with the value of measurement.The PBPK modeling of pravastatin were built successfully in different conditions,fasting and postprandial,because of the values of fold-error<2.0.Conclusion1.PBPK model combined in vivo and in vitro experiments is to research the drug interaction of valsartan and metolazone as well as the diet influence of pitavastatin calcium accurately.Our research provides a referenced research method for the drug interaction and drug diet influence.2.The result of valsartan and metolazone drug combination and drug administration PBPK model in renal damage patients research showes that from the point of view of drug metabolism,valsartan can be combined used with metolazone,and the combine using of them has synergistic effect.3.Kidney damage in a certain extent affect the process of absorption,distribution,metabolism and excretion in human body of metolazone,but it has no effect on the processes above of valsartan.The result of the drug administration in kidney damage patients will play a guiding role in the drug safety in kidney damage patients of metolazone.Prediction and study of drugs interaction based on PBPK model play a positive role in early warning research of pharmacokinetic in Chinese human bodies with diseases and certain eating habits and under other complicated situations,monitoring the clinical drug use process,investigating the influencing factors during the drug use process,and avoiding the drug risks.