Model-based Therapeutic Drug Monitoring:Latamoxef And Ganciclovir

Therapeutic drug monitoring(TDM)is the measurement of specific drugs at timed intervals in order to maintain a relatively constant concentration of the medication in the bloodstream.TDM is used,in combination with parameters of the patient’s clinical condition to help guide decisions regarding drug dosing in individual patients in order to optimize therapeutic efficacy and minimize adverse events.The major barriers in the application of TDM in newborns mainly include restriction in the number(and volume)of blood samples that can be obtained and difficulty in determination of plasma concentration at specific times.The model-based TDM overcomes the disadvantage of traditional TDM,and has become a popular research topic.This new approach for TDM could predict pharmacokinetics parameters based on limited samples and individual patient’s covariates,and is an optimal option for optimizing individual treatment.Incorporation of such an approach into clinical dose individualization can help to optimize efficacy,and decrease the risk of adverse event.Anti-infective drugs are the most commonly used drugs in newborns.Their pharmacokinetics has been observed not only differ greatly between newborns and adults,but also to be highly variable among newborns.This was likely due to the developmental changes which were proved to have a profound impact on the disposition of drugs,and anti-infective drugs are no exception.Off-label and/or unlicensed anti-infective drugs are frequently prescribed for newborns.However,dose extrapolated from adults or pediatric average dose is inadequate for neonatal dosing regimen and might induce side effects or treatment failure,or even contribute to resistance.There is an urgent need to develop appropriate TDM approaches for newborns to maximize therapeutic benefits while minimizing toxicity.Therefore,the model-based TDM is of great significance in neonatal anti-infective treatment.Objective:We sought to develop sensitive analytical method adapted to neonatal TDM,and evaluate its clinical feasibility of TDM of latamoxef in newborns.Furthermore,this study aimed to develop model-based TDM approach using population pharmacokinetics modeling techniques,sensitive analytical methods,and the opportunistic sampling strategy,and confirm the clinical utility of model-based TDM in dosage individualization of ganciclovir in newborns.Methods:In the study of developing an adapted analytical method for TDM of latamoxef in newborns,we develop a microscale high performance liquid chromatography(HPLC)method for the determination of latamoxef in plasma.In order to adapt to perform neonatal TDM and optimize clinical outcome,the volume of plasma was decreased,and the sensitivity of analytical method was increased by simplifying sample preparation process and optimizing chromatographic conditions.After method validation,newborns receiving latamoxef therapy were enrolled in this study.The developed method was applied to routine TDM of latamoxef to evaluate its clinical feasibility in clinical practice and the efficacy of current dosing regimen.In the study of model-based dosage individualization of ganciclovir in newborns,newborns receiving ganciclovir therapy for congenital cytomegalovirus(CMV)infections were enrolled.Samples were collected from blood remaining after routine biochemical tests using an opportunistic sampling strategy.The analytical method of ganciclovir in plasma samples was adapted from Zhang D et al..According to monitoring results,individual AUC0-24 was estimated for each patient after administration of standard dosing regimen using Bayesian estimation based on a published population pharmacokinetic model.The individual dose was adjusted based on the target AUC0-24 and evaluated again to ensure the efficacy.Our aim was to confirm the clinical utility of model-based dosage individualization of ganciclovir in newborns.Results:In the study of developing an adapted analytical method for TDM of latamoxef in newborns,the calibration range was linear from 3 to 60 μg/mL.For quality controls,intra-and inter-day precision(RSD)were less than 15%,in addition,the intra-and inter-day accuracy(deviation)were between 85 and 115%.The lower limit of quantification(LLOQ)was 3 μg/mL.A total of 18 newborns were included in the present study.Eighteen latamoxef trough concentrations were available with a mean value of 9.00 μg/mL(range<LLOQ to 29.66 pg/mL).Four newborns had trough concentration lower than 4 μg/mL,4 newborns 4-8 μg/mL and only one higher than 16 μg/mL.In the study of model-based dosage individualization of ganciclovir in newborns,a total of 26 newborns with congenital CMV infection were included.All patients received standard dosing regimen of 5 mg/kg twice daily(BID).Only 11(42.3%)patients achieved the target AUC0-24 at the standard dose.For all the substantially subtherapeutic(below 80%target AUC0-24)patients(n=5),model-based dosage adjustment was performed using Bayesian estimation,A 28.6%-60%dose increase was performed in these five patients and all adapted AUC0-24 achieved the target(range:48.6-66.1 μg·h/mL).No patients decreased the dose,as no obvious adverse events were observed.Conclusions:A rapid,reliable and highly sensitive HPLC method has been developed for analysis of latamoxef in very small sample volumes,facilitate the application to neonatal TDM.Additionally,the model-based dosing individualization of ganciclovir combined with the opportunistic sampling strategy significantly improved the therapeutic target achievement,and reduced both the number(and volume)of blood samples.This approach was proved more suitable for newborns-a vulnerable population,and would be more acceptable in neonatal clinical practice.