When will the Glomerular Filtration Rate in Former Preterm Neonates Catch up with Their Term Peers?

AIMS: Whether and when glomerular filtration rate (GFR) in preterms catches up with term peers is unknown. This study aims to develop a GFR maturation model for (pre)term-born individuals from birth to 18 years of age. Secondarily, the function is applied to data of different renally excreted drugs. METHODS: We combined published inulin clearance values and serum creatinine (Scr) concentrations in (pre)term born individuals throughout childhood. Inulin clearance was assumed to be equal to GFR, and Scr to reflect creatinine synthesis rate/GFR. We developed a GFR function consisting of GFRbirth (GFR at birth), and an Emax model dependent on PNA (with GFRmax, PNA50 (PNA at which half of GFR max is reached) and Hill coefficient). The final GFR model was applied to predict gentamicin, tobramycin and vancomycin concentrations. RESULT: In the GFR model, GFRbirth varied with birthweight linearly while in the PNA-based Emax equation, GA was the best covariate for PNA50, and current weight for GFRmax. The final model showed that for a child born at 26 weeks GA, absolute GFR is 18%, 63%, 80%, 92% and 96% of the GFR of a child born at 40 weeks GA at 1 month, 6 months, 1 year, 3 years and 12 years, respectively. PopPK models with the GFR maturation equations predicted concentrations of renally cleared antibiotics across (pre)term-born neonates until 18 years well. CONCLUSIONS: GFR of preterm individuals catches up with term peers at around three years of age, implying reduced dosages of renally cleared drugs should be considered below this age.

Predicting Unacceptable Pain in Cardiac Surgery Patients Receiving Morphine Maintenance and Rescue Doses: A Model-Based Pharmacokinetic-Pharmacodynamic Analysis.

BACKGROUND: Optimal analgesic treatment following cardiac surgery is crucial for both patient comfort and successful postoperative recovery. While knowledge of both the pharmacokinetics and pharmacodynamics of analgesics is required to predict optimal drug dosing, models quantifying the pharmacodynamics are scarce. Here, we quantify the pharmacodynamics of morphine by modeling the need for rescue morphine to treat unacceptable pain in 118 patients after cardiac surgery. METHODS: The rescue morphine event data were analyzed with repeated time-to-event (RTTE) modeling using NONMEM. Postoperative pain titration protocol consisted of continuous morphine infusions (median duration 20.5 hours) with paracetamol 4 times daily and rescue morphine in case of unacceptable pain (numerical rating scale ≥4). RESULTS: Patients had a median age of 73 years (interquartile range [IQR]: 63-77) and median bodyweight of 80 kg (IQR: 72-90 kg). Most patients (55%) required at least 1 rescue morphine dose. The hazard for rescue morphine following cardiac surgery was found to be significantly influenced by time after surgery, a day/night cycle with a peak at 23:00 (95% confidence interval [CI], 19:35-02:03) each day, and an effect of morphine concentration with 50% hazard reduction at 9.3 ng·mL-1 (95% CI, 6.7-16). CONCLUSIONS: The pharmacodynamics of morphine after cardiac surgery was successfully quantified using RTTE modeling. Future studies can be used to expand the model to better predict morphine's pharmacodynamics on the individual level and to include the pharmacodynamics of other analgesics so that improved postoperative pain treatment protocols can be developed.

The Influence of Normalization Weight in Population Pharmacokinetic Covariate Models.

In covariate (sub)models of population pharmacokinetic models, most covariates are normalized to the median value; however, for body weight, normalization to 70 kg or 1 kg is often applied. In this article, we illustrate the impact of normalization weight on the precision of population clearance (CLpop) parameter estimates. The influence of normalization weight (70, 1 kg or median weight) on the precision of the CLpop estimate, expressed as relative standard error (RSE), was illustrated using data from a pharmacokinetic study in neonates with a median weight of 2.7 kg. In addition, a simulation study was performed to show the impact of normalization to 70 kg in pharmacokinetic studies with paediatric or obese patients. The RSE of the CLpop parameter estimate in the neonatal dataset was lowest with normalization to median weight (8.1%), compared with normalization to 1 kg (10.5%) or 70 kg (48.8%). Typical clearance (CL) predictions were independent of the normalization weight used. Simulations showed that the increase in RSE of the CLpop estimate with 70 kg normalization was highest in studies with a narrow weight range and a geometric mean weight away from 70 kg. When, instead of normalizing with median weight, a weight outside the observed range is used, the RSE of the CLpop estimate will be inflated, and should therefore not be used for model selection. Instead, established mathematical principles can be used to calculate the RSE of the typical CL (CLTV) at a relevant weight to evaluate the precision of CL predictions.

Drugs Being Eliminated via the Same Pathway Will Not Always Require Similar Pediatric Dose Adjustments.

For scaling drug plasma clearance (CLp) from adults to children, extrapolations of population pharmacokinetic (PopPK) covariate models between drugs sharing an elimination pathway have enabled accelerated development of pediatric models and dosing recommendations. This study aims at identifying conditions for which this approach consistently leads to accurate pathway specific CLp scaling from adults to children for drugs undergoing hepatic metabolism. A physiologically based pharmacokinetic (PBPK) simulation workflow utilizing mechanistic equations defining hepatic metabolism was developed. We found that drugs eliminated via the same pathway require similar pediatric dose adjustments only in specific cases, depending on drugs extraction ratio, unbound fraction, type of binding plasma protein, and the fraction metabolized by the isoenzyme pathway for which CLp is scaled. Overall, between-drug extrapolation of pediatric covariate functions for CLp is mostly applicable to low and intermediate extraction ratio drugs eliminated by one isoenzyme and binding to human serum albumin in children older than 1 month.

Prediction of human CNS pharmacokinetics using a physiologically-based pharmacokinetic modeling approach.

Knowledge of drug concentration-time profiles at the central nervous system (CNS) target-site is critically important for rational development of CNS targeted drugs. Our aim was to translate a recently published comprehensive CNS physiologically-based pharmacokinetic (PBPK) model from rat to human, and to predict drug concentration-time profiles in multiple CNS compartments on available human data of four drugs (acetaminophen, oxycodone, morphine and phenytoin). Values of the system-specific parameters in the rat CNS PBPK model were replaced by corresponding human values. The contribution of active transporters for the four selected drugs was scaled based on differences in expression of the pertinent transporters in both species. Model predictions were evaluated with available pharmacokinetic (PK) data in human brain extracellular fluid and/or cerebrospinal fluid, obtained under physiologically healthy CNS conditions (acetaminophen, oxycodone, and morphine) and under pathophysiological CNS conditions where CNS physiology could be affected (acetaminophen, morphine and phenytoin). The human CNS PBPK model could successfully predict their concentration-time profiles in multiple human CNS compartments in physiological CNS conditions within a 1.6-fold error. Furthermore, the model allowed investigation of the potential underlying mechanisms that can explain differences in CNS PK associated with pathophysiological changes. This analysis supports the relevance of the developed model to allow more effective selection of CNS drug candidates since it enables the prediction of CNS target-site concentrations in humans, which are essential for drug development and patient treatment.

Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults.

BACKGROUND: The clearance of cytochrome P450 (CYP) 3A substrates is reported to be reduced with lower age, inflammation and obesity. As it is unknown what the overall influence is of these factors in the case of obese adolescents vs. morbidly obese adults, we studied covariates influencing the clearance of the CYP3A substrate midazolam in a combined analysis of data from obese adolescents and morbidly obese adults. METHODS: Data from 19 obese adolescents [102.7 kg (62-149.5 kg)] and 20 morbidly obese adults [144 kg (112-186 kg)] receiving intravenous midazolam were analysed, using population pharmacokinetic modelling (NONMEM 7.2). In the covariate analysis, the influence of study group, age, total body weight (TBW), developmental weight (WTfor age and length) and excess body weight (WTexcess = TBW - WTfor age and length) was evaluated. RESULTS: The population mean midazolam clearance was significantly higher in obese adolescents than in morbidly obese adults [0.71 (7%) vs. 0.44 (11%) L/min; p < 0.01]. Moreover, clearance in obese adolescents increased with TBW (p < 0.01), which seemed mainly explained by WTexcess, and for which a so-called 'excess weight' model scaling WTfor age and length to the power of 0.75 and a separate function for WTexcess was proposed. DISCUSSION: We hypothesise that higher midazolam clearance in obese adolescents is explained by less obesity-induced suppression of CYP3A activity, while the increase with WTexcess is explained by increased liver blood flow. The approach characterising the influence of obesity in the paediatric population we propose here may be of value for use in future studies in obese adolescents.

Kernel-Based Visual Hazard Comparison (kbVHC): a Simulation-Free Diagnostic for Parametric Repeated Time-to-Event Models.

Repeated time-to-event (RTTE) models are the preferred method to characterize the repeated occurrence of clinical events. Commonly used diagnostics for parametric RTTE models require representative simulations, which may be difficult to generate in situations with dose titration or informative dropout. Here, we present a novel simulation-free diagnostic tool for parametric RTTE models; the kernel-based visual hazard comparison (kbVHC). The kbVHC aims to evaluate whether the mean predicted hazard rate of a parametric RTTE model is an adequate approximation of the true hazard rate. Because the true hazard rate cannot be directly observed, the predicted hazard is compared to a non-parametric kernel estimator of the hazard rate. With the degree of smoothing of the kernel estimator being determined by its bandwidth, the local kernel bandwidth is set to the lowest value that results in a bootstrap coefficient of variation (CV) of the hazard rate that is equal to or lower than a user-defined target value (CVtarget). The kbVHC was evaluated in simulated scenarios with different number of subjects, hazard rates, CVtarget values, and hazard models (Weibull, Gompertz, and circadian-varying hazard). The kbVHC was able to distinguish between Weibull and Gompertz hazard models, even when the hazard rate was relatively low (< 2 events per subject). Additionally, it was more sensitive than the Kaplan-Meier VPC to detect circadian variation of the hazard rate. An additional useful feature of the kernel estimator is that it can be generated prior to model development to explore the shape of the hazard rate function.

Predicting Drug Concentration-Time Profiles in Multiple CNS Compartments Using a Comprehensive Physiologically-Based Pharmacokinetic Model.

Drug development targeting the central nervous system (CNS) is challenging due to poor predictability of drug concentrations in various CNS compartments. We developed a generic physiologically based pharmacokinetic (PBPK) model for prediction of drug concentrations in physiologically relevant CNS compartments. System-specific and drug-specific model parameters were derived from literature and in silico predictions. The model was validated using detailed concentration-time profiles from 10 drugs in rat plasma, brain extracellular fluid, 2 cerebrospinal fluid sites, and total brain tissue. These drugs, all small molecules, were selected to cover a wide range of physicochemical properties. The concentration-time profiles for these drugs were adequately predicted across the CNS compartments (symmetric mean absolute percentage error for the model prediction was <91%). In conclusion, the developed PBPK model can be used to predict temporal concentration profiles of drugs in multiple relevant CNS compartments, which we consider valuable information for efficient CNS drug development.

Influence of Morbid Obesity on the Pharmacokinetics of Morphine, Morphine-3-Glucuronide, and Morphine-6-Glucuronide.

INTRODUCTION: Obesity is associated with many pathophysiological changes that may result in altered drug metabolism. The aim of this study is to investigate the influence of obesity on the pharmacokinetics of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) through a combined analysis in morbidly obese patients and non-obese healthy volunteers. METHODS: In this analysis, data from 20 morbidly obese patients [mean body mass index 49.9 kg/m2 (range 37.6-78.6 kg/m2) and weight 151.3 kg (range 112-251.9 kg)] and 20 healthy volunteers [mean weight 70.6 kg (range 58-85 kg)] were included. Morbidly obese patients received 10 mg of intravenous (I.V.) morphine after gastric bypass surgery, with additional morphine I.V. doses as needed. Healthy volunteers received an I.V. bolus of morphine of 0.1 mg/kg followed by an infusion of 0.030 mg kg-1 h-1 for 1 h. Population pharmacokinetic modeling was performed using NONMEM 7.2. RESULTS: In morbidly obese patients, elimination clearance of M3G and M6G was decreased substantially compared with healthy volunteers (p < 0.001). Regarding glucuronidation, only a slight decrease in the formation of M6G and a delay in the formation of M3G was found (both p < 0.001). Obesity was also identified as a covariate for the peripheral volume of distribution of morphine (p < 0.001). CONCLUSION: Metabolism of morphine is not altered in morbidly obese patients. However, decreased elimination of both M3G and M6G is evident, resulting in a substantial increase in exposure to these two metabolites. A rational explanation of this finding is that it results from alterations in membrane transporter function and/or expression in the liver. ClinicalTrials.gov identifier: NCT01097148.

Body weight, gender and pregnancy affect enantiomer-specific ketorolac pharmacokinetics.

AIMS: Although ketorolac analgesia is linked only to the S-enantiomer, there is limited information on the stereo-selective pharmacokinetics of this agent. We studied the stereo-selective pharmacokinetics of ketorolac in a pooled dataset of two studies, with women at delivery and 4-5 months postpartum, and males and nonpregnant females. METHODS: Nonlinear mixed-effect modelling was used to evaluate the stereo-selective pharmacokinetics of ketorolac tromethamine after a single intravenous injection immediately after delivery (n = 41), 4-5 months postpartum (n = 8, paired), and in male (n = 12) and nonpregnant female (n = 14) subjects. All of the males and six of the nonpregnant females were recruited from another study, in which they were undergoing blood sampling for 24 h. All remaining cases underwent blood sampling for 8 h. RESULTS: For both the R- and S-enantiomers, body weight affected ketorolac clearance. In addition, clearance for both enantiomers was 36% [95% confidence interval (CI) 15%, 58%] higher in male than in female subjects of the same body weight, and 55% (95% CI 33%, 78%) higher in women at delivery than in nonpregnant women of the same body weight. Women at delivery also had a 27% (95% CI 8%, 46%) higher distribution volume than nonpregnant women. The proportional effects of the covariates were not significantly different for the two ketorolac enantiomers. CONCLUSIONS: Besides the anticipated impact of body weight on clearance, R- and S-ketorolac clearance is increased in male subjects and in women at delivery. To reach an exposure equivalent to that in nonpregnant women, males should receive a 36% increased ketorolac dose and pregnant women a 55% increased dose, in addition to a dose adjustment by body weight.

Dose evaluation of lamivudine in human immunodeficiency virus-infected children aged 5 months to 18 years based on a population pharmacokinetic analysis.

AIM: The objectives of this study were to characterize age-related changes in lamivudine pharmacokinetics in children and evaluate lamivudine exposure, followed by dose recommendations for subgroups in which target steady state area under the daily plasma concentration-time curve (AUC0-24h ) is not reached. METHODS: Population pharmacokinetic modelling was performed in NONMEM using data from two model-building datasets and two external datasets [n = 180 (age 0.4-18 years, body weight 3.4-60.5 kg); 2061 samples (median 12 per child); daily oral dose 60-300 mg (3.9-17.6 mg kg-1 )]. Steady state AUC0-24h was calculated per individual (adult target 8.9 mg·h l-1 ). RESULTS: A two-compartment model with sequential zero order and first order absorption best described the data. Apparent clearance and central volume of distribution (% RSE) were 13.2 l h-1 (4.2%) and 38.9 l (7.0%) for a median individual of 16.6 kg, respectively. Bodyweight was identified as covariate on apparent clearance and volume of distribution using power functions (exponents 0.506 (20.2%) and 0.489 (32.3%), respectively). The external evaluation supported the predictive ability of the final model. In 94.5% and 35.8% of the children with a body weight >14 kg and <14 kg, respectively, the target AUC0-24h was reached. CONCLUSION: Bodyweight best predicted the developmental changes in apparent lamivudine clearance and volume of distribution. For children aged 5 months-18 years with a body weight <14 kg, the dose should be increased from 8 to 10 mg kg-1  day-1 if the adult target for AUC0-24h is aimed for. In order to identify whether bodyweight influences bioavailability, clearance and/or volume of distribution, future analysis including data on intravenously administered lamivudine is needed.

Allometric Scaling of Clearance in Paediatric Patients: When Does the Magic of 0.75 Fade?

Allometric scaling on the basis of bodyweight raised to the power of 0.75 (AS0.75) is frequently used to scale size-related changes in plasma clearance (CLp) from adults to children. A systematic assessment of its applicability is undertaken for scenarios considering size-related changes with and without maturation processes. A physiologically-based pharmacokinetic (PBPK) simulation workflow was developed in R for 12,620 hypothetical drugs. In scenario one, only size-related changes in liver weight, hepatic blood flow, and glomerular filtration were included in simulations of 'true' paediatric CLp. In a second scenario, maturation in unbound microsomal intrinsic clearance (CLint,mic), plasma protein concentration, and haematocrit were also included in these simulated 'true' paediatric CLp values. For both scenarios, the prediction error (PE) of AS0.75-based paediatric CLp predictions was assessed, while, for the first scenario, an allometric exponent was also estimated based on 'true' CLp. In the first scenario, the PE of AS0.75-based paediatric CLp predictions reached up to 278 % in neonates, and the allometric exponent was estimated to range from 0.50 to 1.20 depending on age and drug properties. In the second scenario, the PE sensitivity to drug properties and maturation was higher in the youngest children, with AS0.75 resulting in accurate CLp predictions above 5 years of age. Using PBPK principles, there is no evidence for one unique allometric exponent in paediatric patients, even in scenarios that only consider size-related changes. As PE is most sensitive to the allometric exponent, drug properties and maturation in younger children, AS0.75 leads to increasingly worse predictions with decreasing age.

A Generic Multi-Compartmental CNS Distribution Model Structure for 9 Drugs Allows Prediction of Human Brain Target Site Concentrations.

PURPOSE: Predicting target site drug concentration in the brain is of key importance for the successful development of drugs acting on the central nervous system. We propose a generic mathematical model to describe the pharmacokinetics in brain compartments, and apply this model to predict human brain disposition. METHODS: A mathematical model consisting of several physiological brain compartments in the rat was developed using rich concentration-time profiles from nine structurally diverse drugs in plasma, brain extracellular fluid, and two cerebrospinal fluid compartments. The effect of active drug transporters was also accounted for. Subsequently, the model was translated to predict human concentration-time profiles for acetaminophen and morphine, by scaling or replacing system- and drug-specific parameters in the model. RESULTS: A common model structure was identified that adequately described the rat pharmacokinetic profiles for each of the nine drugs across brain compartments, with good precision of structural model parameters (relative standard error <37.5%). The model predicted the human concentration-time profiles in different brain compartments well (symmetric mean absolute percentage error <90%). CONCLUSIONS: A multi-compartmental brain pharmacokinetic model was developed and its structure could adequately describe data across nine different drugs. The model could be successfully translated to predict human brain concentrations.

Children in clinical trials: towards evidence-based pediatric pharmacotherapy using pharmacokinetic-pharmacodynamic modeling.

INTRODUCTION: In pediatric pharmacotherapy, many drugs are still used off-label, and their efficacy and safety is not well characterized. Different efficacy and safety profiles in children of varying ages may be anticipated, due to developmental changes occurring across pediatric life. AREAS COVERED: Beside pharmacokinetic (PK) studies, pharmacodynamic (PD) studies are urgently needed. Validated PKPD models can be used to derive optimal dosing regimens for children of different ages, which can be evaluated in a prospective study before implementation in clinical practice. Strategies should be developed to ensure that formularies update their drug dosing guidelines regularly according to the most recent advances in research, allowing for clinicians to integrate these guidelines in daily practice. Expert commentary: We anticipate a trend towards a systems-level approach in pediatric modeling to optimally use the information gained in pediatric trials. For this approach, properly designed clinical PKPD studies will remain the backbone of pediatric research.

Morbidly Obese Patients Exhibit Increased CYP2E1-Mediated Oxidation of Acetaminophen.

INTRODUCTION: Acetaminophen (paracetamol) is mainly metabolized via glucuronidation and sulphation, while the minor pathway through cytochrome P450 (CYP) 2E1 is held responsible for hepatotoxicity. In obese patients, CYP2E1 activity is reported to be induced, thereby potentially worsening the safety profile of acetaminophen. The aim of this study was to determine the pharmacokinetics of acetaminophen and its metabolites (glucuronide, sulphate, cysteine and mercapturate) in morbidly obese and non-obese patients. METHODS: Twenty morbidly obese patients (with a median total body weight [TBW] of 140.1 kg [range 106-193.1 kg] and body mass index [BMI] of 45.1 kg/m(2) [40-55.2 kg/m(2)]) and eight non-obese patients (with a TBW of 69.4 kg [53.4-91.7] and BMI of 21.8 kg/m(2) [19.4-27.4]) received 2 g of intravenous acetaminophen. Fifteen blood samples were collected per patient. Population pharmacokinetic modelling was performed using NONMEM. RESULTS: In morbidly obese patients, the median area under the plasma concentration-time curve from 0 to 8 h (AUC0-8h) of acetaminophen was significantly smaller (P = 0.009), while the AUC0-8h ratios of the glucuronide, sulphate and cysteine metabolites to acetaminophen were significantly higher (P = 0.043, 0.004 and 0.010, respectively). In the model, acetaminophen CYP2E1-mediated clearance (cysteine and mercapturate) increased with lean body weight [LBW] (population mean [relative standard error] 0.0185 L/min [15 %], P < 0.01). Moreover, accelerated formation of the cysteine and mercapturate metabolites was found with increasing LBW (P < 0.001). Glucuronidation clearance (0.219 L/min [5 %]) and sulphation clearance (0.0646 L/min [6 %]) also increased with LBW (P < 0.001). CONCLUSION: Obesity leads to lower acetaminophen concentrations and earlier and higher peak concentrations of acetaminophen cysteine and mercapturate. While a higher dose may be anticipated to achieve adequate acetaminophen concentrations, the increased CYP2E1-mediated pathway may preclude this dose adjustment.

Pain and distress caused by endotracheal suctioning in neonates is better quantified by behavioural than physiological items: a comparison based on item response theory modelling.

Pain cannot be directly measured in neonates. Therefore, scores based on indirect behavioural signals such as crying, or physiological signs such as blood pressure, are used to quantify neonatal pain both in clinical practice and in clinical studies. The aim of this study was to determine which of the physiological and behavioural items of 2 validated pain assessment scales (COMFORT and premature infant pain profile) are best able to detect pain during endotracheal and nasal suctioning in ventilated newborns. We analysed a total of 516 PIPP and COMFORT scores from 118 newborns. A graded response model was built to describe the data and item information was calculated for each of the behavioural and physiological items. We found that the graded response model was able to well describe the data, as judged by agreement between the observed data and model simulations. Furthermore, a good agreement was found between the pain estimated by the graded response model and the investigator-assessed visual analogue scale scores (Spearman rho correlation coefficient = 0.80). The information scores for the behavioural items ranged from 1.4 to 27.2 and from 0.0282 to 0.131 for physiological items. In these data with mild to moderate pain levels, behavioural items were vastly more informative of pain and distress than were physiological items. The items that were the most informative of pain are COMFORT items "calmness/agitation," "alertness," and "facial tension."

Structure-Based Prediction of Anti-infective Drug Concentrations in the Human Lung Epithelial Lining Fluid.

PURPOSE: Obtaining pharmacologically relevant exposure levels of antibiotics in the epithelial lining fluid (ELF) is of critical importance to ensure optimal treatment of lung infections. Our objectives were to develop a model for the prediction of the ELF-plasma concentration ratio (EPR) of antibiotics based on their chemical structure descriptors (CSDs). METHODS: EPR data was obtained by aggregating ELF and plasma concentrations from historical clinical studies investigating antibiotics and associated agents. An elastic net regularized regression model was used to predict EPRs based on a large number of CSDs. The model was tuned using leave-one-drug-out cross validation, and the predictions were further evaluated using a test dataset. RESULTS: EPR data of 56 unique compounds was included. A high degree of variability in EPRs both between- and within drugs was apparent. No trends related to study design or pharmacokinetic factors could be identified. The model predicted 80% of the within-drug variability (R(2) WDV) and 78.6% of drugs were within 3-fold difference from the observations. Key CSDs were related to molecular size and lipophilicity. When predicting EPRs for a test dataset the R(2) WDV was 75%. CONCLUSIONS: This model is of relevance to inform dose selection and optimization during antibiotic drug development of agents targeting lung infections.

Towards Rational Dosing Algorithms for Vancomycin in Neonates and Infants Based on Population Pharmacokinetic Modeling.

Because of the recent awareness that vancomycin doses should aim to meet a target area under the concentration-time curve (AUC) instead of trough concentrations, more aggressive dosing regimens are warranted also in the pediatric population. In this study, both neonatal and pediatric pharmacokinetic models for vancomycin were externally evaluated and subsequently used to derive model-based dosing algorithms for neonates, infants, and children. For the external validation, predictions from previously published pharmacokinetic models were compared to new data. Simulations were performed in order to evaluate current dosing regimens and to propose a model-based dosing algorithm. The AUC/MIC over 24 h (AUC24/MIC) was evaluated for all investigated dosing schedules (target of >400), without any concentration exceeding 40 mg/liter. Both the neonatal and pediatric models of vancomycin performed well in the external data sets, resulting in concentrations that were predicted correctly and without bias. For neonates, a dosing algorithm based on body weight at birth and postnatal age is proposed, with daily doses divided over three to four doses. For infants aged <1 year, doses between 32 and 60 mg/kg/day over four doses are proposed, while above 1 year of age, 60 mg/kg/day seems appropriate. As the time to reach steady-state concentrations varies from 155 h in preterm infants to 36 h in children aged >1 year, an initial loading dose is proposed. Based on the externally validated neonatal and pediatric vancomycin models, novel dosing algorithms are proposed for neonates and children aged <1 year. For children aged 1 year and older, the currently advised maintenance dose of 60 mg/kg/day seems appropriate.