Population Pharmacokinetics,Effectiveness And Safety Of ?-lactams In Neonates With Spesis Based On Real-world Data And PK/PD Model

BackgroundGlobally,the newborn population has become the "severe disaster area" for off-label drug use.Most studies have shown that the proportion of hospitalized newborns who have at least one-time off-label drug use exceeds 90%.Anti-infective drugs are the most common prescription.More than 70%of hospitalized newborns have received anti-infective treatment within three days after birth,and anti-infective drugs are also the most prone to off-label use.Sepsis is a disease with high morbidity and mortality in neonates and it is mainly treated with anti-infective drugs.The off-label use of drugs cannot guarantee the efficacy of the drugs and may increase the risk of adverse drug reactions.The direct reason for off-label use is the lack of information on neonatal indications and dosages in the drug labels,and the root cause is that it is difficult to carry out clinical trials in neonates,resulting in pharmacokinetics,effectiveness,and safety data missing in the drug approval and review process.In order to accelerate the development and regulate the application of medication in pediatric patients,the Center for Drug Evaluation of the National Medical Products Administration issued the"Technical guidelines for the development and evaluation of children's drugs supported by real-world evidence(draft for comment)","Model-guided drug research and development technology guidelines" and other related documents.Regulatory agencies encourage to promote children's drugs' development and application by using the real-world data and model technology,and to carry out the standardization and supplementation of the "children's medication" information in the drug labels.Therefore,this study aimed to develop the pharmacokinetics,effectiveness and safety of anti-infective drugs in patients with neonatal sepsis based on real-world data and pharmacokinetics/pharmacodynamics(PK/PD)models,so that to supplement neonatal data and provide optimized dosing regimens.Moreover,this study aimed to clarify the feasibility of the drug dosing regimens based on real-world studies and PK/PD models,add reasonable usage to pediatrics in labels,and provide ideas to decrease the off-label use of commonly used drugs in pediatrics.Part 1:Pharmacokinetics and dosage optimization of ?-lactams based on PK/PD models in neonates with early-onset sepsisPurposes:Early-onset sepsis(EOS)is one of the most common diseases in the neonates that occurs within 72 hours after birth.It has a high morbidity and mortality rate.Since the physiology of neonates changes rapidly after birth,the clinical symptoms of EOS are atypical.Laboratory indicators are insensitive,nonspecific,and particular diagnostic markers are lacking.Besides,blood culture results are usually lagging and the positive incidence is low.These peculiarities increase the difficulty of the diagnosis and treatment of EOS.The international guidelines recommended penicillins and aminoglycosides to treat EOS.However,the pathogenic bacteria and drug susceptibility of EOS in Chinese neonates are significantly different from those in other countries and regions.In addition,the aminoglycoside antibiotics are banned in children younger than six years old in China.So the empirical anti-infective treatment is common in clinical practice.However,most anti-infective drugs are off-label and lack a safe and effective dosing regimen for EOS treatment.Therefore,this study aimed to take the data of anti-infective drugs in clinical practice as the entry point and systematically analyze the population pharmacokinetic characteristics of azlocillin,amoxicillin,piperacillin and cefotaxime in neonates,and establish optimized dosing regimens based on the PK/PD models.Methods:The study was a prospective,open study.The neonates who were treated with azlocillin or amoxicillin for empirical anti-infective treatment were included.Plasma samples were collected by using an opportunistic sampling method.The drug concentrations were determined by high-performance liquid chromatography.Population pharmacokinetics models were established by NONMEM software and the the dosing regimens were optimized by Monte Carlo simulation.In addition,the mature population pharmacokinetics models of piperacillin and cefotaxime reported in the literature were used to optimize the dosing regimens.Results:A total of 95 neonates treated with azlocillin were enrolled,and 167 plasma drug concentrations were used to establish the population pharmacokinetic model of azlocillin.The drug concentrations ranged from below the lowest limit of quantification to 397.2 ?g/mL.A one-compartment model with first-level elimination characteristics and covariates of current weight,birth weight and postnatal age could best describe the population pharmacokinetics of azlocillin in neonates,and the median value of clearance rate of azlocillin was 0.13 L/h/kg.A total of 187 neonates treated with amoxicillin were enrolled,and 224 plasma concentrations were used to establish the population pharmacokinetic model of amoxicillin.The drug concentrations ranged from below the lowest limit of quantification to 73.6 ?g/mL.A two-compartment model with first-level elimination characteristics and covariates of current weight,postnatal age and gestational age could best describe the population pharmacokinetics of amoxicillin in neonates,and the median value of clearance rate of amoxicillin was 0.25 L/h/kg.The models established in this study were used to optimize the dose of azlocillin and amoxicillin,and the published models were used to optimize the dose of piperacillin and cefotaxime.The optimized dosage regimens were:azlocillin,100 mg/kg,q8h;piperacillin,80 mg/kg,q8h;cefotaxime,50 mg/kg,q12h;amoxicillin,25 mg/kg,q12h.Conclusions:Population pharmacokinetic models of azlocillin and amoxicillin were established in neonates,and optimized dosing regimens of azlocillin,amoxicillin,piperacillin and cefotaxime were recommended based on the PK/PD model.Part 2:Effectiveness of optimized dosing regimens of ?-lactams based on PK/PD model in neonates with early-onset sepsisPurposes:In the anti-infective drug labels,the lack of EOS dosing regimens results from the lack of population pharmacokinetics,effectiveness and safety data in neonatal EOS patients.The population pharmacokinetic model were established based on the off-label use data used in clinical practice and the optimized dosing regimens based on PK/PD models were obtained.However,the effectiveness of the optimized dosing regimens in clinical practice was unknown.Therefore,this study aimed to explore the effectiveness of the optimized dosing regimens and clarify the dosing regimens' value based on PK/PD models.Methods:The study was a prospective,open study.Neonates with EOS were enrolled.The dosing regimens were:azlocillin,100 mg/kg,q8h;piperacillin,80 mg/kg,q8h;cefotaxime,50 mg/kg,q12h;amoxicillin,25 mg/kg,q12h.Effectiveness outcomes included clinical treatment failure rate and pharmacodynamics(PD)target.Besides,the duration of anti-infective treatment and the time to start anti-infective treatment after birth were also evaluated.Results:In this study,45,75,49,and 51 neonates completed the treatment of azlocillin,amoxicillin,piperacillin,and cefotaxime,respectively and were included in effectiveness analysis.The clinical treatment failure rates of azlocillin,amoxicillin,piperacillin,and cefotaxime were 2.2%(n=1),10.7%(n=8),16.3%(n=8)and 2.0%(n=1),respectively.The PD target were 95.6%(n=43),85.3%(n=64),95.9%(n=47)and 100.0%(n=51),respectively,which were all higher than 85%.The average treatment duration of 4 drugs was 98-180 hours,and anti-infective treatment was performed within 24 hours after birth on average.Conclusions:This study confirmed the value of the PK/PD model-guided dosing regimens in clinical practice.The optimized dosing regimens of anti-infective drugs based on the PK/PD model was adequate for EOS treatment.Part 3:Safety of ?-lactams in neonates based on big dataPurposes:The off-label use of drugs for neonates is challenging to ensure the therapeutic effect of the drug and may increase the risk of adverse drug reactions.Studies have reported that the incidence of adverse drug reactions in children and neonates is two times and four times that of adults.Most anti-infective drugs commonly used in neonates lack safety information,laying dangers for safe use.Clinical trials often fail to obtain sufficient safety data due to the small sample size.Therefore,this study aimed to analyze the use of anti-infective drugs in neonates through a big data study,and supplement their safety data in neonates.Methods:This study was a retrospective,big-data study.Through the cloud health big data platform of Shandong Province,the electronic medical records of hospitalized neonates who were?91 days old and undergoing anti-infection treatment from 2012-2019 were obtained.Data of neonates with severe congenital deformities and undergoing surgery were excluded.The data of demographic,medication and safety during the medication were grabbed.The use of anti-infective drugs and the incidence of drug possible related adverse events in neonates were analyzed.Results:The study analyzed the use of 10 common anti-infective drugs(amoxicillin,ceftazidime,meloxicillin,cefotaxime,ceftriaxone,piperacillin,meropenem,penicillin,cefepime and cefoperazone),including six medical units and a total of 8232 neonates.Amoxicillin used the most in neonates,accounting for 31.1%,followed by ceftazidime(23.0%)and mezlocillin(18.1%);penicillin,cefepime and cefoperazone were all used less than 2%.According to the WHO Essential Medicines List Access,Watch,and Reserve(AWaRe)classification,the total proportion of anti-infective drugs in the Access group,Watch group and Reserve group were 43%,56%and 1%,respectively.The proportion of the Watch group increased year by year,and the proportion exceeded 70%in the past three years.In addition,this study completed the safety assessment of 10 anti-infective drugs in neonates and supplemented the safety data.The results showed that the incidence of gastrointestinal symptoms was 8.23%-24.7%,which was ranked first among the adverse events of 10 anti-infective drugs.Other drug possible related adverse events such as skin rash,anemia,leukopenia,thrombocytopenia and thrombocytosis were also more common,with incidences of 1.89%-7.86%,0.86%-13.94%,0.37%-2.22%,0.37%-1.29%and 0.29%-5.92%,respectively.Conclusions:This study analyzed the use of anti-infective drugs in neonates,supplemented the neonatal safety data of 10 anti-infective drugs,and provided data support for anti-infective treatment.