| BackgroundThe processes affecting the tissue concentration of drugs over time include absorption,distribution,metabolism and elimination(ADME).The maturation process of the kidney,the primary organ responsible for drug elimination,could cause drug clearance change in children of different ages,which in turn has an impact on the dosage adjustment of this drug.Elimination of drug in renal mainly depends on glomerular filtration,the maturation process of which begins already during fetal organogenesis and completes by childhood.Ceftazidime is a thirdgeneration cephalosporin antibiotic which is widely used in clinical practice for the targeted and empirical treatment of various bacterial infections in children.It is not metabolized and excreted directly through the kidney,and there is a significant correlation between its plasma drug clearance and the maturation of renal function.So it can be used as a probe drug to describe renal maturation.The range of recommended dosage for pediatric patients in the current ceftazidime instructions is large and unspecified for the indication,and the actual used dose is inconsistent between clinical centers and guidelines or instructions,as well as between different clinical centers,which can easily lead to drug resistance and adverse events.Most published population pharmacokinetics studies of ceftazidime in pediatric patients focused on a specific age group with a single disease,and studies that can more fully evaluate the effects of renal maturation or other factors on its pharmacokinetic parameters are lacking.Therefore,it is necessary to develop a ceftazidime population pharmacokinetic model encompassing a wider age range based on the renal maturation model,and to optimize the dosing of ceftazidime in children of different ages by using this model.ObjectiveThis study was aimed to consider the effects of renal maturation and other factors on the population pharmacokinetics of ceftazidime based on renal maturation model in children,and to evaluate and optimize the dosage of ceftazidime in different age groups by using the model,in addition to providing data to describe the maturation of glomerular filtration.MethodsThis study was an open-label population pharmacokinetic study in preterm and full-term neonates,infants,toddlers and children and approved by the institutional ethics board of the clinical centers.Basic information,dosing information and biochemical parameters of children were collected in detail,and ceftazidime plasma samples were obtained by opportunistic sampling method and determined using high performance liquid chromatography-ultraviolet detection or ultra performance liquid chromatography-tandem mass spectrometry method.Population pharmacokinetic model were developed using a nonlinear mixed-effect modeling approach to describe the effects of growth-and maturation-related changes in renal function on the population pharmacokinetics of ceftazidime by different equations for covariates.After model validation,Monte Carlo simulations were used for dosing evaluation and optimization in different age groups.ResultsFinally 323 children were included.Five hundred and ninety-five ceftazidime plasma concentrations were used for population pharmacokinetic analysis.The model was a twocompartment model with first-order elimination.The effect of renal function maturation on ceftazidime population pharmacokinetics parameters was described by an allometric model for body weight combined with a maturation model for postmenstrual age.In addition,different data sources,cystic fibrosis and creatinine clearance also had significantly effect on the model.The dosing evaluation and optimization results showed that the target attainment of neonates with early-onset sepsis was 64.2%for a MIC of 8 mg/L given 30 mg/kg q12h.Infants and children with pneumonia could achieve 74.1%and 68.2%target attainment for a MIC of 8 mg/L given 50 mg/kg q8h,respectively.Neonates with late-onset sepsis could achieve 68.5%target attainment for a MIC of 16 mg/L given 50 mg/kg q8h.In children with cystic fibrosis,a higher dose(50 mg/kg,q8h)or continuous infusion was required to achieve a higher target attainment.ConclusionIn this study,a population pharmacokinetics model of ceftazidime in preterm and full-term neonates,infants,toddlers and children was established based on renal maturation model in children,and dosage regimen for children of different ages were recommended based on pharmacokinetic-pharmacodynamic theory. |
