Maturational changes in vancomycin protein binding affect vancomycin dosing in neonates

Leroux, Stéphanie; Anker, Johannes N. van den; Smits, Anne; Pfister, Marc; Allegaert, Karel

doi:10.1111/bcp.13899

Cited by 16 publications

(14 citation statements)

References 9 publications

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“…When aiming for a similar unbound vancomycin exposure in neonates as in adults, a total AUC 24h /MIC≥267 target (400 x 0.67) should be applied, derived from an unbound fraction of 0.67 in adults versus 0.9 in neonates. PK simulations hereby observed that 54.2% of neonates achieved the AUC 24h /MIC≥400 target, while 91.2% achieved the AUC 24h /MIC≥267 target (unbound target approach) [89]. Besides between-population differences, a large variability in vancomycin protein binding is observed within the neonatal population [15].…”

Section: Vancomycin Protein Binding: Not Total But Free Concentrationmentioning

confidence: 83%

Pharmacokinetic modelling and Bayesian estimation-assisted decision tools to optimize vancomycin dosage in neonates: only one piece of the puzzle

Allegaert

Flint

Smits

2019

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Vancomycin is commonly administered to neonates, while observational data on therapeutic drug monitoring (TDM, trough levels) suggest that vancomycin exposure and dosage remain substandard.Area covered: Data on vancomycin pharmacokinetics (PK) and its covariates are abundant. Consequently, modelling is an obvious tool to improve targeted exposure, with a shift from TDM trough levels to area under the curve (AUC 24h ) targets, as in adults. Continuous administration appeared as practice to facilitate AUC 24h target attainment, while Bayesian model-supported targeting emerged as novel tool.However, the AUC 24h /MIC (minimal inhibitory concentration) target itself should consider neonate specific aspects (bloodstream infections, coagulase-negative staphylococci, protein binding, underexplored causes of variability, like assays, preparation and administration inaccuracies, or missing covariates). Expert opinion:To improve targeted exposure in neonates, initial vancomycin prescription should be based on 'a priori model based individual dosing' using validated dosing regimens, followed by further tailoring by dosing optimization applying Bayesian estimation-assisted TDM. Future research should focus on feasibility to integrate these tools (individualized dosing, Bayesian models) in clinical practice, and to perform PK/PD studies in the relevant animal models and human neonatal setting (coagulase-negative staphylococci, blood stream infections).

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Section: Vancomycin Protein Binding: Not Total But Free Concentrationmentioning

confidence: 83%

Pharmacokinetic modelling and Bayesian estimation-assisted decision tools to optimize vancomycin dosage in neonates: only one piece of the puzzle

Allegaert

Flint

Smits

2019

Expert Opinion on Drug Metabolism & Toxicology

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“…This was based on the fact that the protein binding of ceftobiprole in adults is relatively low and independent of drug concentration, as well as the lack of available neonatal and pediatric protein binding data. However, we are aware that for some other antibiotics, higher unbound drug fractions in neonates and/or children are observed compared to adults ( 25 – 29 ). The lack of measured unbound concentrations is a study limitation.…”

Section: Discussionmentioning

confidence: 99%

Model-Based Approach for Optimizing Ceftobiprole Dosage in Pediatric Patients

Rubino

Cammarata

Smits

et al. 2021

Antimicrob Agents Chemother

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Ceftobiprole is an advanced-generation cephalosporin for intravenous administration with activity against Gram-positive and Gram-negative organisms. A population pharmacokinetic (PK) model characterizing the disposition of ceftobiprole in plasma using data from patients in three pediatric studies was developed. Model-based simulations were subsequently performed to assist in dose optimization for the treatment of pediatric patients with hospital-acquired or community-acquired pneumonia. The population PK dataset comprised 518 ceftobiprole plasma concentrations from 107 patients aged 0 (birth) to 17 years. Ceftobiprole PK was well described by a three-compartment model with linear elimination. Ceftobiprole clearance was modeled as a function of glomerular filtration rate; other PK parameters were scaled to body weight. The final population PK model provided a robust and reliable description of the PK of ceftobiprole in the pediatric study population. Model-based simulations using the final model suggested that a ceftobiprole dose of 15 mg/kg infused over 2 hours and administered every 12 hours in neonates and infants <3 months or every 8 hours in older pediatric patients would result in a ceftobiprole exposure consistent with that in adults and good pharmacokinetic-pharmacodynamic target attainment. The dose should be reduced to 10 mg/kg every 12 hours in neonates and infants <3 months who weigh <4 kg to avoid high exposures. Extended intervals and reduced doses may be required for pediatric patients older than 3 months of age with renal impairment.

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“…Reduced protein binding increases the free concentration and thus the free fraction of drugs, thereby enhancing the capacity of the active drug to more easily diffuse to other compartments 25 . On the one hand, this will result in more free, active drug available to bind and modulate with receptors, but it also will increase the clearance rate of the drug (see below) 26 . Moreover, when higher free fractions of a given compound are circulating in the plasma compartment, these fractions are able to penetrate to deeper tissue compartments, resulting in a higher distribution volume.…”

Section: Summary Of Relevant Factors That Influence Drug Disposition mentioning

confidence: 99%

Considerations for Drug Dosing in Premature Infants

Anker

Allegaert

2021

The Journal of Clinical Pharma

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In premature infants, effective and safe drug therapy depends on optimal dose selection and requires a thorough understanding of the underlying disease(s) of these fragile infants as well as the pharmacokinetics and pharmacodynamics of the drugs selected to treat their diseases. Differences in gestational and postnatal age or weight are the major determinants of the observed variability in drug disposition and effect in these infants. This article presents an outline on how to translate the results of a population pharmacokinetic/pharmacodynamic study into rational dosing regimens, and how physiologically based pharmacokinetic modeling, electronic health records, and the abundantly available data of vital functions of premature infants during their stay in the neonatal intensive care unit for evaluation of their pharmacotherapy can be used to tailor the most safe and effective dose in these infants.

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Maturational changes in vancomycin protein binding affect vancomycin dosing in neonates

Cited by 16 publications

References 9 publications

Pharmacokinetic modelling and Bayesian estimation-assisted decision tools to optimize vancomycin dosage in neonates: only one piece of the puzzle

Pharmacokinetic modelling and Bayesian estimation-assisted decision tools to optimize vancomycin dosage in neonates: only one piece of the puzzle

Model-Based Approach for Optimizing Ceftobiprole Dosage in Pediatric Patients

Considerations for Drug Dosing in Premature Infants

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