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AIMSVancomycin is one of the most evaluated antibiotics in neonates using modeling and simulation approaches. However no clear consensus on optimal dosing has been achieved. The objective of the present study was to perform an external evaluation of published models, in order to test their predictive performances in an independent dataset and to identify the possible study-related factors influencing the transferability of pharmacokinetic models to different clinical settings. METHODPublished neonatal vancomycin pharmacokinetic models were screened from the literature. The predictive performance of six models was evaluated using an independent dataset (112 concentrations from 78 neonates). The evaluation procedures used simulation-based diagnostics [visual predictive check (VPC) and normalized prediction distribution errors (NPDE)]. RESULTSDifferences in predictive performances of models for vancomycin pharmacokinetics in neonates were found. The mean of NPDE for six evaluated models were 1.35, -0.22, -0.36, 0.24, 0.66 and 0.48, respectively. These differences were explained, at least partly, by taking into account the method used to measure serum creatinine concentrations. The adult conversion factor of 1.3 (enzymatic to Jaffé) was tested with an improvement in the VPC and NPDE, but it still needs to be evaluated and validated in neonates. Differences were also identified between analytical methods for vancomycin. CONCLUSIONThe importance of analytical techniques for serum creatinine concentrations and vancomycin as predictors of vancomycin concentrations in neonates have been confirmed. Dosage individualization of vancomycin in neonates should consider not only patients' characteristics and clinical conditions, but also the methods used to measure serum creatinine and vancomycin. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Population pharmacokinetics of vancomycin have been widely studied in neonates.• Many covariates including bodyweight, gestational age and post-natal age, renal function, co-administered drugs, etc. have been evaluated and some of them are associated with inter-individual pharmacokinetic variability. WHAT THIS STUDY ADDS• The analytical technique used for measuring serum creatinine concentrations has been confirmed as a study-related factor influencing the transferability of published models to different clinical settings.• Different predictive performances were demonstrated between analytical methods (FPIA and EMIT).• The neonatal conversion factor of serum creatinine concentrations between the Jaffé and enzymatic methods and the interferences/cross-reactivity of analytical methods need to be evaluated in neonates in future studies.

Background and Objectives Uncertainty exists regarding the optimal dosing regimen for vancomycin in different patient populations, leading to a plethora of subgroup-specific pharmacokinetic models and derived dosing regimens. We aimed to investigate whether a single model for vancomycin could be developed based on a broad dataset covering the extremes of patient characteristics. Furthermore, as a benchmark for current dosing recommendations, we evaluated and optimised the expected vancomycin exposure throughout life and for specific patient subgroups. Methods A pooled population-pharmacokinetic model was built in NONMEM based on data from 14 different studies in different patient populations. Steady-state exposure was simulated and compared across patient subgroups for two US Food and Drug Administration/European Medicines Agency-approved drug labels and optimised doses were derived. Results The final model uses postmenstrual age, weight and serum creatinine as covariates. A 35-year-old, 70-kg patient with a serum creatinine level of 0.83 mg dL −1 (73.4 µmol L −1) has a V 1 , V 2 , CL and Q 2 of 42.9 L, 41.7 L, 4.10 L h −1 and 3.22 L h −1. Clearance matures with age, reaching 50% of the maximal value (5.31 L h −1 70 kg −1) at 46.4 weeks postmenstrual age then declines with age to 50% at 61.6 years. Current dosing guidelines failed to achieve satisfactory steady-state exposure across patient subgroups. After optimisation, increased doses for the Food and Drug Administration label achieve consistent target attainment with minimal (± 20%) risk of under-and over-dosing across patient subgroups. Conclusions A population model was developed that is useful for further development of age and kidney function-stratified dosing regimens of vancomycin and for individualisation of treatment through therapeutic drug monitoring and Bayesian forecasting.

The present study determined the pharmacokinetic profile of vancomycin in premature Malaysian infants. A one-compartment infusion model with first-order elimination was fitted to serum vancomycin concentration data (n ‫؍‬ 835 points) obtained retrospectively from the drug monitoring records of 116 premature newborn infants. Vancomycin concentrations were estimated by a fluorescence polarization immunoassay. Population and individual estimates of clearance and distribution volume and the factors which affected the variability observed for the values of these parameters were obtained using a population pharmacokinetic modeling approach. The predictive performance of the population model was evaluated by visual inspections of diagnostic plots and nonparametric bootstrapping with replacement. Dosing guidelines targeting a value of >400 for the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC 24 /MIC ratio) were explored using Monte Carlo simulation. Body size (weight), postmenstrual age, and smallfor-gestational-age status are important factors explaining the between-subject variability of vancomycin pharmacokinetic parameter values for premature neonates. The typical population parameter estimates of clearance and distribution volume for a 1-kg premature appropriate-for-gestational-age neonate with a postmenstrual age of 30 weeks were 0.0426 liters/h and 0.523 liters, respectively. There was a 20% reduction in clearance for small-for-gestational-age infants compared to the level for the appropriate-for-gestational-age control. Dosage regimens based on a priori target response values were formulated. In conclusion, the pharmacokinetic parameter values for vancomycin in premature Malaysian neonates were estimated. Improved dosage regimens based on a priori target response values were formulated by incorporating body size, postmenstrual age, and small-for-gestational-age status, using Monte Carlo simulations with the modelestimated pharmacokinetic parameter values.Bacterial sepsis is a major cause of neonatal complications, prolonged hospital stay, and death in premature newborns, especially those in developing countries. Sepsis-related mortality and morbidity rates were even higher in extremely preterm neonates and intrauterine-growth-restricted infants because of their innate immunological immaturity (36). Because coagulase-negative staphylococcus (CoNS) is a common pathogen for late-onset (72-h-postbirth) septicemia, and because methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen (10), vancomycin continues to be widely prescribed in neonatal intensive care units.Kidney and vestibular/cochlear damage is a concern associated with vancomycin use. Very recently, it was shown that vancomycin trough concentrations were correlated with nephrotoxicity in hospitalized adult patients (27). Nonetheless, vancomycin-associated ototoxicity and nephrotoxicity among neonates are thought to be less frequent than those in adults (11), although more evidence-based i...