Quantitative Administration Studies Of Ertapenem And Daptomycin In Children With Renal Impairment Based On PBPK Model

Objective1.To establish physiologically based pharmacokinetic（PBPK）models of ertapenem and daptomycin in healthy adults and healthy children.2.To establish PBPK models of ertapenem and daptomycin in adults with renal impairment and children with renal impairment.3.To predict the pharmacokinetic changes of ertapenem and daptomycin in children with renal impairment.4.To develop the dosage adjustment plan for ertapenem and daptomycin in children with renal impairment.5.To evaluate the pharmacodynamic of ertapenem and daptomycin.Methods1.The pharmacokinetic parameters and published pharmacokinetic data of ertapenem and daptomycin were collected according to literatures,and the drug-time curve of ertapenem and daptomycin in the literatures were obtained by Getdata Graph Digitizer.2.Identify the model type of each organ/tissue and establish the PBPK model framework that links each organ/tissue with the hemodynamics.3.Gastro Plus^?software was used to simulate the PK curves of healthy people under different dosing schedules,and establish PBPK models of ertapenem and daptomycin in healthy population.4.Comprehensive verification of the accuracy and reliability of the PBPK models for healthy population based on the results of single-dose administration,multiple-dose administration,and population simulations:（1）Evaluate the compliance of the simulated drug-time curve with the measured data points;（2）Compare the fold error of the corresponding PK parameters.5.Based on the PBPK model of healthy population,the pathophysiological parameters changes related to renal insufficiency were took into account,and the PBPK model of adults with renal impairment was established to predict the pharmacokinetic behavior of ertapenem and daptomycin in this special population.6.Comprehensive verification of the accuracy and reliability of the PBPK models for adults with renal impairment based on the results of single-dose administration,multiple-dose administration,and population simulations:（1）Evaluate the compliance of the simulated drug-time curve with the measured data points;（2）Compare the fold error of the corresponding PK parameters.7.Optimize the PBPK model for adults with renal impairment,and analyze the changes in the main physiological parameters that affect the pharmacokinetic changes between adults with renal impairment and healthy adults.8.With the software built-in PBPK model of children with renal impairment,which based on physiological changes of growth and development as well as the changes of renal function,the changes in the main physiological parameters affecting pharmacokinetic changes between adults with renal impairment and healthy adults are included.9.Predict the pharmacokinetic changes of ertapenem and daptomycin in children with renal impairment,and make a dosage adjustment plan.10.Perform the Monte Carlo simulation to evaluate pharmacodynamic of ertapenem and daptomycin according to%T>MIC or AUC/MIC by Crystal Ball software combine the population simulation from Gastroplus^?.Results1.PBPK models of ertapenem and daptomycin in healthy population were established.After different dosage regimens（Ertapenem:0.5 g,1 g,2 g,3 g for adults;15 mg/kg,20 mg/kg,40 mg/kg for children.Daptomycin:4 mg/kg,6 mg/kg,8 mg/kg,10 mg/kg,12 mg/kg for adults;4 mg/kg,5 mg/kg,7 mg/kg,9 mg/kg,10 mg/kg,12mg/kg for children.）,the agreement was well between predicted and observed drug concentration–time profiles,the prediction accuracy for the pharmacokinetic parameters was further assessed.The most of the fold error values of areas under the concentration-time curve（AUC）and maximum concentration(C_max)were around 1.2 or below and all were within the 2-fold error range.2.PBPK models of ertapenem and daptomycin in adults with renal impairment were established.After dosage regimens:1 g ertapenem or 10 mg/kg daptomycin,the agreement was well between predicted and observed drug concentration–time profiles,the prediction accuracy for the pharmacokinetic parameters was further assessed.The most of the fold error values of areas under the concentration-time curve（AUC）and maximum concentration(C_max)were around 1.2 or below and all were within the 2-fold error range.3.PBPK models of ertapenem and daptomycin in children with renal impairment were established.Predict the pharmacokinetic changes of ertapenem and daptomycin in children with renal impairment:（1）The C_maxwas not signifificantly changed in pediatric patients with renal impairment compared to healthy children.However,the AUC was 1.42-fold,1.84-fold,2.37-fold,and 3.52-fold higher in mild,moderate,severe renal impairment,and end-stage renal disease than that in healthy children,respectively.（2）Similar to the results for adults with different degrees of renal function,the C_maxand AUC of daptomycin in children with mild-to-moderate renal impairment did not significantly differ from those in healthy children.The AUC increased by an average of1.55-fold and 1.85-fold in severe renal impairment and end-stage renal disease,respectively,and changes were greater than 2-fold in younger children.4.Optimized the dosage of ertapenem and daptomycin in children with renal impairment.（1）In pediatric patients with mild,moderate,and severe renal impairment and end-stage renal disease,the recommended dosage of ertapenem should be reduced to 13 mg/kg b.i.d,9 mg/kg b.i.d,6 mg/kg b.i.d,and 5 mg/kg b.i.d,respectively.（2）In pediatric patients with mild-to-moderate renal impairment,no dosage adjustments were needed.In pediatric patients with severe renal impairment,the dosing interval should be extended（from q24h to q48h）.In patients with end-stage renal disease combined with c SSSI,the daptomycin dose of 9 mg/kg q24h should be adjusted to 7 mg/kg q48h in children aged 2-6 years,and 10 mg/kg q24h should be adjusted to 6 mg/kg q48h in children aged 1-2 years.For S.aureus bacteremia,12 mg/kg q24h should be adjusted to8 mg/kg q48h in children aged 1-6 years.5.According to the results of pharmacodynamic evaluation,the adjusted dose of ertapenem and daptomycin in children with renal impairment can also achieve satisfactory antibacterial effects.Simulation results show that the steady-state C_minof daptomycin may be above 24.3 mg/L in a few cases,which may lead to an increase in creatine phosphokinase and even rhabdomyolysis,therefore,CPK should be closely monitored more than once a week in pediatric patients with renal impairment.Conlusions1.The PBPK models of ertapenem and daptomycin in healthy populaiton and people with renal impairment were established in this study were basically accurate and reliable.2.We designed dose adjustments for children of different ages and different renal function states based on the PBPK models,and it will provide a reference for clinical individualized administration.