Vancomycin dosing in neonates: enhancing outcomes using population pharmacokinetics and simulation.

The following are my responses to the comments of Professors Anderson & Holford (henceforth mentioned as A & H in the text) on my manuscript entitled: ‘Evaluation of a morphine maturation model for the prediction of morphine clearance in children’[1].

Intravenous (i.v.) paracetamol (acetaminophen) is gaining increasing use in neonates (1–3), despite an off-label status in some countries. Product information for i.v. paracetamol does not consider the clearance maturation with age in neonates in its dosing recommendations. In Australasia the same dose of 15 mgAEkg 6 h is suggested for neonates over 10 days of age and for infants and children up to 33 kg. A reduced dose of 7.5 mgAEkg 6 h is proposed in term neonates <10 days of age. In Europe there is no labeled use for neonates <10 days of age. The registered dose is 7.5 mgAEkg 6 h for neonates after 10 days of age through to infants of 10 kg. A dose of 15 mgAEkg 6 h (max daily dose 60 mgAEkg) is recommended between 10 and 40 kg. These dosing regimens suggest something magic about 10 days. There are data concerning the pharmacokinetics of this formulation in neonates. Population pharmacokinetics of the i.v. prodrug (propacetamol) have been studied in neonates following single (4,5) and repeat dose administration (6). Parameter estimates from neonates given repeat doses of i.v. paracetamol over a median of 4 days duration are consistent with those estimated using propacetamol (7). Dosing regimens used in some institutions for neonates have been published in Pediatric Anesthesia (2,8), but there are few data validating the safety or effectiveness of these regimens. The idea that a target effect and associated target concentration can be used to make rational individual dose decisions has acceptance (9). A knowledge of neonatal pharmacokinetics assists with dose prediction to achieve the target concentration. There are, however, flaws and constraints of current knowledge that limit implementation of this approach to dosing.

The objective of this study is to evaluate the predictive performance of several models to predict drug clearance in preterm and term neonates. Five models using different types of allometric and linear models were developed. Two sets of data were used to develop these models (data from preterm neonates to adults and data from preterm and term neonates). Models were also developed with (normalized to 70kg) or without body weight normalization (body weight 1kg). From the literature, clearance values for four drugs from neonates to adults were obtained. External data were used to evaluate the predictive performance of these models in preterm and term neonates. The results of the study indicated that (1) normalization to a standard body weight had no impact on the predictive performance of the models, (2) the model developed from preterm neonates to adults using fixed exponent 0.75 provided inaccurate estimate (overestimation) of drug clearance in neonates, (3) a far superior prediction of clearance was observed with the model when the exponents of allometry were estimated than the model using exponent 0.75, (4) linear models with the exception of the model with intercept provided comparable results to the estimated exponent model and were superior in their predictive performance to the model using exponent 0.75, and (5) when the models were developed from neonate data, the predictive performance of all models were similar. Overall, the study indicated that body weight normalization had no impact on the performance of model prediction, the exponents of allometry in pharmacostatistical models should be estimated rather than fixed, and more studies are needed to evaluate the suitability of linear models for the prediction of drug clearance in neonates.

Seizures are the most common neurologic emergency in neonates and are associated with significant morbidity and mortality. Current first‐line pharmacotherapy, phenobarbital, is associated with serious adverse effects, including impairment of the developing brain. Levetiracetam is a well‐tolerated alternative; however, its use is limited because its optimal dosing in neonates remains unknown. Additionally, limited knowledge of levetiracetam pharmacokinetics in neonates, especially preterm neonates, means they generally receive the same weight‐based dosing. This may put preterm neonates at risk of increased adverse events or insufficient drug effects. This study developed a physiologically based pharmacokinetic (PBPK) model for levetiracetam in term and preterm neonates to evaluate their pharmacokinetic differences. After accounting for the physiological changes, a 1.56‐fold increase in drug tissue distribution was needed to represent the increased volume of distribution of levetiracetam in neonates. In term neonates, scaling renal clearance from children based on estimated glomerular filtration rate required a 61% increase to accurately describe renal clearance. Additionally, allometric scaling to extrapolate metabolic clearance required age‐dependent corrections to account for the reduced metabolic clearance. In preterm neonates, extrapolated renal clearance was approximately equal to observed total clearance, suggesting renal clearance as the sole elimination route. Consistently, predicted metabolic clearance approached zero when the postmenstrual age was <37.5 weeks. Our simulations showed that common intravenous levetiracetam dosing regimens resulted in higher plasma concentrations in more premature neonates or those with reduced kidney function. In preterm neonates, these regimens may result in plasma concentrations exceeding toxicity thresholds, indicating a need for lower weight‐based dosing.

Vancomycin dosing in neonates is challenging due to developmental pharmacokinetic variability. The study was to characterize vancomycin pharmacokinetics in a large cohort of preterm and term neonates and develop individualized dosing regimens. A 5-year retrospective study of a cohort of 255 neonates was included. An allometric one-compartment model with first-order elimination best described the vancomycin concentrations. The population pharmacokinetic estimates (between subject variability) of clearance (CL) and volume of distribution (V) were 2.58 L·h-1·70 kg-1 (9.00 %) and 52.09 L·70 kg-1 (29.00%), respectively. CL and V were significantly influenced by body weight and postmenstrual age. Vancomycin CL reached 50% of adult values at 43.6 weeks PMA (a sigmoid Emax model). Renal maturation, estimated by creatinine production rate, was a significant covariate. Bayesian-guided individualized dosage regimens were developed and evaluated. Vancomycin overdosage should be avoided in very young premature babies (PMA = 25 weeks). Optimization of efficacy while minimizing toxicity of vancomycin in preterm and term neonates is needed, especially guided by personalized body weight, postmenstrual age, and renal function.

Background Discrepancies in vancomycin AUC24 estimates across population pharmacokinetic (popPK) models raise concerns about their impact on dosing recommendations and probability of target attainment (PTA) after multiple therapeutic drug monitoring (TDM) occasions. This study assesses model selection’s impact on model-based dosing and PTA following simulated TDM occasions and explores predictors of PTA. Research design and methods Using a virtual neonatal population and 15 validated vancomycin popPK models, TDM events were simulated with initial dosing, followed by Bayesian-guided adjustments over three TDM occasions. The number of non-therapeutic patients was compared across models, and associations between model characteristics and simulated PTA were explored. Results Across models, geometric mean (gMean) AUC24 values varied: 496 mg·h/L (35.7% geometric coefficient of variation, gCV) for the first TDM, 570 mg·h/L (53.1% gCV) for the second, and 484 mg·h/L (62.2% gCV) for the third. Non-therapeutic patients ranged from 0 (Mulubwa et al.) to 530 (Allegaert et al.). Interindividual variability in clearance correlated with non-therapeutic patients (R2 = 0.88), while residual variability showed no correlation. Conclusion Model selection affects simulated vancomycin AUC24 values and PTA in neonates, influencing dosing decisions. These findings highlight model characteristics correlating with target attainment.

First-dose and steady-state population pharmacokinetics and pharmacodynamics of piperacillin by continuous or intermittent dosing in critically ill patients with sepsis

<h3>Objectives</h3> Vancomycin is a glycopeptide antibiotic commonly used in neonatal intensive care units (NICUs) to treat late onset sepsis. It is recommended that vancomycin trough levels at steady state following intermittent dosing regimen be maintained at 10–20 mg/L, which is largely dependent on the type of infection. Our objective is to assess the ability of initial vancomycin dosing regimens to obtain target trough levels and to assess the percentage and risk factors associated with the development of acute kidney injury (AKI) while on vancomycin. <h3>Methods</h3> This is a retrospective review of all NICU patients admitted between January 2016 and December 2017 who received vancomycin according to the NeoFax at either 10 mg/kg/dose (low-dose group, LDG) or 15 mg/kg/dose (high-dose group, HDG), with a frequency based on the postmenstrual age (PMA) and postnatal age (PNA). Both regimens were compared by their ability to attain target trough levels and the episodes of vancomycin-induced AKI. Other outcomes included identification of risk factors associated with the development of vancomycin-induced nephrotoxicity. <h3>Results</h3> Of 182 patients evaluated, 44 (24%) were in the LDG and 138 patients (76%) were in the HDG. Ninety-one patients (50%) attained target trough levels of 10–20 mg/L. Among these and according to patients’ PMA, 48% in the HDG versus 7% in the LDG in PMA ≤29 weeks and 69% in the HDG versus 18% in the LDG in PMA 30–36 weeks attained target trough levels (p=0.006 and p&lt;0.001, respectively). According to PNA, 47% in the HDG versus none in the LDG in patients &lt;7 days old and 61% in the HDG versus 10% in the LDG in patients aged 8–14 days attained target trough levels (p=0.025 and p=0.016, respectively). A total of 14% developed AKI in the LDG vs 7% in the HDG (p=0.225). Only PMA ≤29 weeks (OR, 4.5, 95% CI 1.5 to 13), vancomycin trough levels &gt;20 mg/L (OR 5.1, 95% CI 1.5 to 17), hypotension (OR 11.02, 95% CI 3.5 to 34) and furosemide (OR 4.4, 95% CI 1.4 to 13.5) were significantly associated with vancomycin-induced AKI in our NICU. <h3>Conclusion</h3> Vancomycin dosing in neonates according to the NeoFax did not provide sufficient attainment of target trough levels (10–20 mg/L). However, using the higher dosing range at 15 mg/kg/dose was more likely to reach target levels, with no measured increased risk of nephrotoxicity. Extreme premature neonates, supratherapeutic vancomycin trough levels, hypotension and furosemide use are associated with an increased incidence of vancomycin-induced nephrotoxicity.

Background: The decision to extubate a preterm neonate relies primarily on clinical judgment and ventilatory parameters. NICUs vary significantly in their periextubation practices, including timing of extubation, postextubation respiratory support and criteria for reintubation. Previous studies have evaluated the risk factors associated with extubation failure. However, currently there is no objective estimator that can calculate the probability of successful extubation for any individual patient. &nbsp; Aim:The aim of this study is to calculate extubation readiness estimator score before extubation and to determine association between periextubation clinical characteristics and ventilator parameters associated with failed extubation. &nbsp; Material and Methods:A prospective observational study was conducted among 68 neonates in R L Jalappa Hospital &amp; Research Centre, a tertiary care centre in Kolar. The principal investigator collected the data of gestational age, birth weight, complete antenatal steroid course(ANS),mode of delivery, sex, silverman anderson score(SAS), surfactant administration after birth, maternal pregnancy induced hypertension(PIH), age, post menstrual age(PMA), weight at extubation, pre-extubation ventilator index, pH,PCO2,FiO, RSS, ventilation rate,MAP, PIP, postextubation respiratory support (CPAP/HFNC), use of caffeine before extubation, use of steroid for extubation. &nbsp; Results: Out of 68 preterm infants, 51.5% were female babies. The mean gestational age of the infant was observed to be 31.01 ± 1.67 weeks. Among the 68 infants, 64.7% were successfully extubated.In multivariable binary logistic regression analysis, gestational age and post menstrual age at extubation significantly (p&lt;0.05) predicted the extubation failure. As the gestational age increases, there is a lower chance of having failed extubation. With the increase in post menstrual age at extubation, there is a higher odd of having failed extubation. &nbsp; Conclusion: The study recommends incorporating the ERE score into routine clinical practice for preterm neonates undergoing extubation, as it can assist healthcare providers in making informed decisions and potentially reduce the risk of complications associated with failed extubation. Monitoring periextubation ventilator parameters and clinical indicators closely can help identify neonates at risk for extubation failure and intervene proactively.

The aim of this study was to describe the population pharmacokinetics (PK) of gentamicin in neonates with suspected or proven Gram-negative sepsis and determine the optimal dosage regimen in relation to the bacterial MICs found in this population. Data were prospectively collected between October 2012 and January 2013 in the Neonatal Intensive Care Unit (NICU) at the Academic Medical Center (AMC), Amsterdam, The Netherlands. A single nonlinear mixed-effects regression analysis (NONMEM) was performed to describe the population PK of gentamicin. Dosage regimens based upon gestational age (GA) were generated using Monte Carlo simulations with the final model. Target values were based on the MIC distribution in our patient population. In total, 136 gentamicin concentrations from 65 (pre)term neonates were included. The PK was best described by an allometric 2-compartment model with postmenstrual age (PMA) as a covariate on clearance (Cl). The MIC distribution (median, 0.75 [range, 0.5 to 1.5] mg/liter) justified a gentamicin target peak concentration of 8 to 12 mg/liter. This study describes the PK of gentamicin in (pre)term neonates. Dosage regimens of 5 mg/kg of body weight every 48 h, 5 mg/kg every 36 h, and 5 mg/kg every 24 h for patients with GAs of <37 weeks, 37 to 40 weeks, and ≥40 weeks, respectively, are recommended.

Premature infants, born before 37 weeks of gestation can have alterations in neurodevelopment and cognition, even when no anatomical lesions are evident. Resting-state functional neuroimaging of naturally sleeping babies has shown altered connectivity patterns, but there is limited evidence on the developmental trajectories of functional organization in preterm neonates. By using a large dataset from the developing Human Connectome Project, we explored the differences in graph theory properties between at-term (n = 332) and preterm (n = 115) neonates at term-equivalent age, considering the age subgroups proposed by the World Health Organization for premature birth. Leveraging the longitudinal follow-up for some preterm participants, we characterized the developmental trajectories for preterm and at-term neonates, for this purpose linear, quadratic, and log-linear mixed models were constructed with gestational age at scan as an independent fixed-effect variable and random effects were added for the intercept and subject ID. Significance was defined at p < 0.05, and the model with the lowest Akaike Information Criterion (AIC) was selected as the best model. We found significant differences between groups in connectivity strength, clustering coefficient, characteristic path length and global efficiency. Specifically, at term-equivalent ages, higher connectivity, clustering coefficient and efficiency are identified for neonates born at later postmenstrual ages. Similarly, the characteristic path length showed the inverse pattern. These results were consistent for a variety of connectivity thresholds at both the global (whole brain) and local level (brain regions). The brain regions with the greatest differences between groups include primary sensory and motor regions and the precuneus which may relate to the risk factors for sensorimotor and behavioral deficits associated with premature birth. Our results also show non-linear developmental trajectories for premature neonates, but decreased integration and segregation even at term-equivalent age. Overall, our results confirm altered functional connectivity, integration and segregation properties of the premature brain despite showing rapid maturation after birth.

The study objective was to evaluate meropenem population pharmacokinetics and pharmacodynamics in nonobese, obese, and morbidly obese patients. Forty adult patients-11 nonobese (body mass index [BMI] < 30 kg/m2 ), 9 obese (30 kg/m2 ≤ BMI < 40kg/m2 ), and 20 morbidly obese (BMI ≥ 40kg/m2 )-received meropenem 500 mg every 6 hours (q6h), q8h, or q12h or 1 g q6h or q8h, infused over 0.5 hour. Population pharmacokinetic modeling was performed using NONMEM, and 5000-patient Monte-Carlo simulations were performed to calculate probability of target attainment (PTA) for 5 dosing regimens, infused over 0.5 and 3 hours, using fT>MIC of 40%, 54%, and 100% of the dosing interval. A 2-compartment linear-elimination model best described the serum concentration-time data, and creatinine clearance was significantly associated with systemic clearance. Pharmacokinetic parameters were not significantly different among patient groups. In patients with creatinine clearances ≥50 mL/min, all simulated dosing regimens achieved >90% PTA at 40% fT>MIC in all patient groups at MICs ≤2 mg/L. Only 500 mg q8h, infused over 0.5 hour, did not achieve >90% PTA at 54% fT>MIC in nonobese and morbidly obese patients. At 100% fT>MIC, 1 g q6h and 2 g q8h, infused over 3 hours, reliably achieved >90% PTA in all patient groups. Meropenem pharmacokinetics are comparable among nonobese, obese, and morbidly obese patients. Standard dosing regimens provide adequate pharmacodynamic exposures for susceptible pathogens at 40% and 54% fT>MIC, but prolonged infusions of larger doses are needed for adequate exposures at 100% fT>MIC. Dosage adjustments based solely on body weight are unnecessary.

Posaconazole (PCZ) plays a crucial role in the prophylaxis and treatment of invasive fungal infections in hematologic malignancies. PCZ concentrations reportedly vary among patients receiving delayed-release tablets (DRT). However, the factors influencing these concentrations remain insufficiently elucidated. Therefore, this study aimed to evaluate the factors influencing PCZ concentrations and their effect on the probability of target attainment (PTA) using a population pharmacokinetic (PPK) approach. We also explored the relationship between PCZ exposure and hepatotoxicity. This retrospective study included adult patients with hematologic malignancies who received PCZ DRT. A PPK model was developed based on observational data for 130 concentrations in 28 patients. Simulation analyses were performed to assess the PTA at standard doses of 0.7 and 1.0 mg/L for prophylaxis and treatment, respectively. Estimated concentrations were used to evaluate the correlation between PCZ exposure and hepatotoxicity. Significant factors influencing PCZ concentrations included body weight, serum total protein levels, and diarrhea. Diarrhea correlated with decreased PCZ concentrations resulting in up to 26% lower PTA compared with that without diarrhea. Moreover, PTA declined markedly as the total protein levels decreased from 6.6 g/dL to 4.4 g/dL. The incidence of hepatotoxicity was 17.4% (4/23); no significant relationship could be established between the PCZ concentrations and hepatotoxicity ( P = 0.188). We identified the factors affecting PCZ exposure, which could not be detected by PPK analysis using data from clinical trials. Our results suggest that the generally recommended dose of PCZ causes underexposure in patients with hematologic malignancies characterized by high body weight, hypoproteinemia, or concurrent diarrhea. Therapeutic drug monitoring for DRT may be recommended, especially in patients with these risk factors.

Piperacillin-tazobactam is widely used off-label in neonates for the empirical treatment of severe infections, resulting in diverse dosing regimens across clinical settings. This variability, combined with high interindividual differences in renal maturation that impact drug disposition, complicates standardized dosing and emphasizes the need for individualized, evidence-based strategies. This study aimed to develop and evaluate a population pharmacokinetic model of piperacillin in neonates to support optimized initial dosing recommendations. Neonatal patients (postnatal age ≤28 days) admitted to an intensive care unit who received piperacillin-tazobactam (8:1 ratio) at Neofax-recommended doses were included. Plasma concentrations were measured using an ultra-high-performance liquid chromatography with tandem mass spectrometry method. Population pharmacokinetic analysis for piperacillin was performed using nonlinear mixed-effects modeling. A total of 65 blood samples were collected from 25 neonates, both preterm (56%) and full-term. Piperacillin pharmacokinetics was best described by a one-compartment model incorporating body weight-based allometric scaling, postmenstrual age, and serum creatinine as covariates influencing clearance. For a typical neonate in the study (1.76 kg), the estimated clearance was 0.748 L/h (coefficient of variation, 38.3%), and the volume of distribution was 0.866 L (37.7%). Simulations indicated adequate probability of target attainment with current recommendations, but a high proportion of preterm neonates (>75%) were at risk of overexposure (trough piperacillin plasma concentration >50 mg/L). Additional simulations supported individualized initial regimens based on renal maturation and suggested that extended infusions (1-4 h) may improve target attainment for stricter targets and less-susceptible pathogens. This study provides a validated pharmacokinetic model for piperacillin in neonates with severe infections, offering a framework to optimize empiric dosing based on renal function and developmental stage.

Developing tailored dosing recommendations for ciprofloxacin in critically ill children using a population approach based on total and unbound concentrations.