论文部分内容阅读
Background: The distribution of renal function and its effect on drug elimination was not well understood in Chinese population, which impeded the clinical therapeutics for Chinese patients as well as the localization of new drugs from global companies.None of current methods to evaluate renal function is ideal except for some methods using exogenous compounds (such as inulin, 99mTc-DTPA, 51Cr-EDTA, 125I-iothalamate) as probe.However, these compounds didnt show any clinical therapeutic effect for the limitation of application in patients to evaluate the renal function.Ceftizoxime was reported not metabolized in liver and excreted virtually (nearly 80%) unchanged by kidney in 24 hours, a few was actively secreted by MRP4 transporter.Ceffizoxime was selected as the probe drug to explore the distribution of renal function and its effect on drug elimination in Chinese population.Aim:To find the distribution of renal function and its effect on drug elimination in Chinese population.Method:A total of 22 Subjects aged from 18-90y including both females and males were infused with 0.5g Ceftizoxime intravenously within half an hour.Blood and urine were sampled according to the scheduled time, and were determined for the concentration of Ceftizoxime as well as genotype analysis of MRP4.These PK/PG data were analyzed by NCA(Non-Compartment Analysis) method followed with population method using NONMEN Ⅶ interfaced with PsN.Results:ANOVA method was used to account the difference, p-value of gender effect on AUC, Cmax, CL, V,CLrwere 0.023, 0.002, 0.02,<0.001,0.27, respectively; and the p-value of age effect has small difference (AUC:0.045, Cmax:0.31, CL:0.043, V:0.66,CLr:<0.001).After constructing base Pop-PK model using 2 compartment with log addictive error model as residual error model, varies of possible covariates indicating general information (e.g., Age, Gender, LBW, BMI, BSA, ALB), renal function(mGFR, eGFR),liver function (e.g., ALP, ALT, AST) and genotype were explored.The final Pop-PK model was validated by VPC method.Conclusion: Population pharmacokinetic analysis showed that gender and genotype also contributed to drug elimination except for GFR.The effect of GFR was quantitatively determined by Pop-PK method.We hope the developed Pop-PK model will be applied in future renal studies in Chinese population.