Effects Of Low-fat Diet And Itraconazole On Pharmacokinetics Of Pyrotinib: Clinical Trial And PBPK Modeling Simulation

Background and Objective Pyrotinib is an irreversible HER2,EGFR dual target tyrosine kinase inhibitor,which was developed by Hengrui,Jiangsu,listed in China in 2018,mainly used in the treatment of HER2 positive breast cancer.Pyrotinib shows good results in the treatment of HER2-positive breast cancer,but in addition to pharmacological effects of drug itself,food and drugs may also affect the treatment of drugs and safety.It is also an important part of new drug research and development.This thesis explores the effects of low-fat diet and itraconazole,a strong CYP3A4 inhibitor,on the pharmacokinetics and safety of pyrotinib based on the needs of new drug development of pyrotinib,and integrates in vivo and in vitro data of pyrotinib to establish a PBPK model of pyrotinib for drug-drug interaction assessment,which is applied to predict the drug interaction between pyrotinib and other CYP3A4 inhibitors,and provide a reference for pyrotinib.This study provides a reference basis for the rational clinical use of pyrotinib.Methods（1）The study of low-fat diet on pyrotinib pharmacokinetics and safety effects was a single center,random,open,single dose,two cycle,two sequences,cross-controlled clinical trials.Sixteen healthy subjects were scheduled to be divided into two groups with 8 subjects per group.Subjects in one group received a single oral administration of400 mg pyrotinib in fasting state on day 1 and 400 mg pyrotinib after meal on day10.The other group received a reverse treatment.Pharmacokinetic blood samples were collected and the concentrations of pyrotinib in the blood samples were measured by LC-MS/MS,pharmacokinetic parameters were calculated using Win Nonlin and the differences in pharmacokinetic parameters between the different dosing methods were calculated.（2）The impact of itraconazole on pyrotinib and safety was an open-label,randomized,self-control study.Eighteen healthy adults were included in this trial.They received a single 80 mg dose of pyrotinib orally on days 1 and 9,and a 200 mg once-daily dose of itraconazole on days 6 through 22.Blood samples were obtained,and the drug concentration was detected using liquid chromatography/tandem mass spectrometry.（3）The PBPK model of pyrotinib was developed on PK-Sim software and the model was validated with data from clinical DDI studies of pyrotinib and itraconazole.The validated model of PBPK of pyrotinib was used to predict the pharmacokinetic interactions of pyrotinib with other CYP3A4 inhibitors（the strong inhibitor clarithromycin,the moderate inhibitors erythromycin and fluvoxamine,and the weak inhibitor cimetidine）and to provide a reference for the rational clinical use of pyrotinib.Results（1）In the pharmacokinetic evaluation of low fat diet for pyrotinib,the geometric mean ratios and 90%confidence intervals of C_max,AUC_0-tand AUC_0-∞compared with fasting administration were 1.39（1.22,1.58）,1.23（1.10,1.37）and 1.23（1.10,1.37）,respectively.The CTCAE classification of this study was grade 1.There were no serious adverse events and no adverse events resulting in death.（2）Compared with 80 mg pyrotinib single dose,200 mg itraconazole combined with 80mg pyrotinib significantly increased the exposure,C_max,AUC_0-tand AUC_0-∞increased by 2.78 times,10.8 times and 10.4 times,respectively,suggesting that under the action of CYP3A4 inhibitory agent itraconazole,the exposure amount of pyrotinib was significantly affected.No serious adverse events occurred during the trial.（3）The PBPK model was successfully verified by clinical test data,which made the model can be used to extrapolate the DDI study without clinical trial.Extrapolation results showed that when combined with pyrotinib,the mean values of C_maxR and AUCR of clarithromycin were 3.85 and 14.82,the mean values of C_maxR and AUCR of erythromycin were 2.76 and 6.58,the mean values of C_maxR and AUCR of fluvoxamine were 1.24 and 1.47,respectively.The mean values of C_maxR and AUCR of cimetidine were 1.22 and 1.26,respectively.Conclusion The low-fat diet has limited effect on the exposure of pyrotinib in humans.Combined with the results of the high-fat diet clinical trial,it is recommended that pyrotinib remain in the postprandial dosing mode.Itraconazole greatly increases the exposure of pyrotinib in humans.Combined with the predicted results of the PBPK model,pyrotinib should be avoided in combination with strong and moderate inhibitors of CYP3A4 during clinical application,and no dose adjustment is required when combined with weak inhibitors of CYP3A4.