Study On The Effect Of CYP450 Enzyme Gene Polymorphisms And Combination Of Drugs On The Blood Concentrations Of Pirfenidone

Objective:Pirfenidone（PFD）is an anti-fibrotic drug with a high incidence of adverse reactions（ADRs）,significant inter-individual variability,and many potential drug-drug interactions.Currently,there is a lack of clinical evidence and assays to support precise dosing of PFD.Therefore,this study aims to analyze the relationship between concentrations and ADRs of PFD.The study will also focus on the effects of CYP450enzyme gene polymorphisms and co-administered drugs on PFD concentrations and ADRs.The aim of this analysis is to provide evidence to support rational and individualized drug use.Methods:1.High-performance liquid chromatography（HPLC）was utilized to establish and validate an in vivo analysis method for PFD.2.Patients who met the inclusion criteria from January 2022 to December 2022 at our institution were recruited.They were genotyped by SNP direct sequencing,and their PFD concentrations were detected by HPLC.Clinical data such as patients’basic personal information,disease and medication information,biochemical indicators including liver and kidney function,and ADRs information were collected and analyzed using SPSS 27 statistical software.Results:1.The established method for in vivo analysis of PFD,with all indexes conforming to national standards,showed a good linear relationship between PFD in the concentrations range of 0.15～37.44μg/m L and peak area,and the standard curve regression equation:Y=17.1100X-0.1259（r²=0.999）,which met the clinical requirements.2.Forty-four patients were included in the study,and the PFD concentrations showed a trend of 500 or 600 mg>400 mg>300 mg>200 mg.3.The ROC curve of PFD concentrations predicting ADRs occurrence suggested that the steady-state valley concentrations of PFD taken as 3.1782μg·m L^-1 had the highest predictive value for ADRs with a sensitivity of 36.8%,specificity of 96.0%,and the area under the curve of ROC was 0.701（95%CI:0.546～0.856）.4.Patients with CYP1A2（rs762551）mutant pure AA had lower PFD C/D than C carriers（CC+AC）[（1.28±0.85）μg/m L vs.（2.03±1.28）μg/m L,P=0.036].5.The incidence of ADRs in the CYP1A2（rs762551）AA group（28.0%）was significantly lower than that in the C carrier（CC+AC）group（63.2%）,P=0.020,and the incidence of ADRs in the allele A carrier（AC+AA）group（35.1%）was significantly lower than that in the CC group（85.7%）,P=0.039.6.No differences were observed for CYP1A2*1C（rs2069514）,2C19（rs4244285,rs4986893）,2D6（rs3892097,rs1065852）,and 2C9（rs1799853,rs1057910）on PFD concentrations and ADRs.7.The PFD concentration/dose（C/D）in the combined lansoprazole/rabeprazole group was lower than that in the non-combined group[0.96（0.51,1.88）μg/m L vs.1.48（1.02,3.21）μg/m L,P=0.030].8.The case study found that the PFD C/D was significantly higher in patients who received combined（intravenous/oral）voriconazole treatment than in those who did not,P<0.01.Similarly,the PFD C/D was significantly higher in patients who received combined esaconazole treatment than in those who did not,P<0.001.There was a significant positive correlation between the PFD C/D and voriconazole steady-state trough concentration（r_s=0.633,P=0.037）.Conclusion:ADRs of PFD were positively correlated with higher PFD concentrations.Additionally,individuals with CYP1A2（rs762551）type AA were associated with lower PFD concentrations and experienced fewer ADRs.What’s more,co-administration of lansoprazole/rabeprazole was associated with lower PFD concentrations.The combination of voriconazole and esaconazole may be associated with higher PFD concentrations.