Comparative Analysis Of Pharmacokinetic Characteristics Of 5 New Drugs Taken Orally By Patients With Chronic Viral Hepatitis And Nonalcoholic Steatohepatitis And Healthy People

Objectives:Pharmacokinetic plays an important role in the research of new drugs by studying the process of absorption,distribution,metabolism and excretion of drugs in the body and their changes.In this study,we in patients with chronic viral hepatitis and nonalcoholic fatty hepatitis patients and healthy subjects using 4 kinds of chronic viral hepatitis treatment drugs and 1 kind of nonalcoholic fatty hepatitis after drug pharmacokinetic data analysis,the characteristics can provide guidance for the selection of effective dose and safe dose in clinical trials of new drugs for chronic viral hepatitis and non-alcoholic steatohepatitis..Methods:A total of 215 adult subjects were enrolled in this study,including 110healthy adults,54 patients with chronic hepatitis B,42 patients with chronic hepatitis C,and 9 patients with nonalcoholic steatohepatitis.The experimental drugs were 4 new drugs for the treatment of chronic viral hepatitis（Pradefovir,GLS4,KW-136 and Fopitasvir）and 1 new drug for non-alcoholic steatohepatitis（ZSP1601）.Among them,Pradefovir and GLS4JHS were selected as new drugs for the treatment of hepatitis B,and KW-136 and Fopitasvir were selected as new drugs for the treatment of hepatitis C.Pradefovir and KW-136 were divided into three dose groups.GLS4,Fopitasvir and ZSP1601 were all single dose groups.In this study,a validated LC-MS/MS method was used to detect and analyze the plasma concentrations of the experimental drugs.Statistical analysis was performed using SAS statistical analysis software version 9.4.The main pharmacokinetic parameters are:Peak concentration(C_max),area under the plasma concentration-time curve from first administration to t hours(AUC_0-t),area under the plasma concentration-time curve from first administration to infinity(AUC_0-∞),peak time(T_max),elimination half-life(t_1/2),and oral clearance rate（Cl/F）.Results:（1）C_max,AUC_0-tand AUC_0-∞:According to the pharmacokinetic parameters of subjects after single oral administration of Pradefovir,GLS4,KW-136 and Fopitasvir,it can be concluded that under the condition of oral administration of the same dose of drugs,the C_max,AUC_0-tand AUC_0-∞of healthy subjects are all greater than those of patients with chronic viral hepatitis.In patients with chronic viral hepatitis,C_maxdecreased by 10%～41%,AUC_0-tdecreased by 14%～41%,AUC_0-∞decreased by 14%～43%.With the increase of experimental drug dose,the decrease range of C_max,AUC_0-tand AUC_0-∞in patients with chronic viral hepatitis in different dosage groups of Pradefovir and KW-136 was gradually increased compared with that of healthy subjects,and the corresponding P value became smaller and smaller.C_max:As the dose increased,the P values of Pradefovir were 0.33,0.21 and0.06,and the decrease values were 25%,32%and 41%,respectively.The P values of KW-136 were 0.23,0.25 and 0.05,and the decrease values were 27%,16%and 30%,respectively.AUC0-t:As the dose increased,the P values of Pradefovir were 0.32,0.21 and 0.01,and the decrease values were 14%,27%and 40%,respectively;as the dose increased,the P values of KW-136 were0.06,0.03 and 0.01,and the decrease values were 41%,39%and 38%,respectively.According to the pharmacokinetic parameters of the subjects after oral administration of ZSP1601,the C_max,AUC_0-tand AUC_0-∞of the healthy subjects were greater than those of the NASH patients at the same oral dose of the drug.In NASH patients,C_maxis reduced by 22%～39%,AUC_0-tis reduced by 16%～45%,and AUC_0-∞is reduced by 18%～44%.（2）T_max,t_1/2:According to the pharmacokinetic parameters of the subjects after oral administration of Pradefovir,GLS4,KW-136 and Fopitasvir,the T_maxof the healthy subjects was greater than that of the patients with chronic viral hepatitis at the same oral dose,while the T_1/2of the healthy subjects was less than that of the patients with chronic viral hepatitis,but the difference was small.According to the pharmacokinetic parameters of subjects after oral administration of ZSP1601,there was no significant difference in T_maxand t_1/2between healthy subjects and NASH patients at the same oral dose of the drug.Conclusion:In this study,the exposure of new drugs for chronic viral hepatitis and non-alcoholic steatohepatitis in patients with chronic hepatitis and non-alcoholic steatohepatitis was lower than that of healthy subjects,and the decrease range was greater with the increase of drug dose in patients with chronic viral hepatitis.