A Survey of Neonatal Pharmacokinetic and Pharmacodynamic Studies in Pediatric Drug Development

Wang, J; Avant, Debbie; Green, D; Seo, Shirley; Fisher, J. Edward; Mulberg, AE; McCune, SK; Gj, Burckart

doi:10.1002/cpt.149

Cited by 32 publications

(29 citation statements)

References 13 publications

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“…Traditionally, the antimicrobial pharmacokinetic study in neonates was focused on average drug exposure to achieve adult levels, and the neonatal recommended dose is usually administered on a milligramper-kilogram basis (10). This approach obviously simplifies the analysis of developmental changes in drug disposition and the effects of clinical conditions on pharmacokinetic parameters.…”

Section: Discussionmentioning

confidence: 99%

Clinical Utility and Safety of a Model-Based Patient-Tailored Dose of Vancomycin in Neonates

Leroux

Jacqz-Aigrain

Biran

et al. 2016

Antimicrob Agents Chemother

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N eonatal bacterial sepsis, exacerbated by neonatal immunodeficiency (1), remains a major cause of mortality and morbidity in newborns (2). Vancomycin is widely used for the treatment of late-onset sepsis caused by methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci in neonatal intensive care units (NICUs) (3); however, the clinical use of vancomycin is still hampered by its narrow therapeutic index and high pharmacokinetic variability (4). Indeed, de Hoog et al. reported that vancomycin clearance and half-life varied between 0.63 and 1.4 ml/ kg/min and between 3.5 and 10 h in neonates, respectively (4). The common adverse effects of vancomycin are nephrotoxicity and ototoxicity; however, it has been shown that neonates tolerated vancomycin better than adults. Safety data for a high dosing regimen and long-term follow-up are still lacking.The pharmacokinetic modeling approach is often applied to evaluate and optimize antimicrobial therapy in neonates (5). To date, vancomycin is one of the best-studied antimicrobials, and numerous studies have been conducted to characterize its pharmacokinetic parameters and to identify individual factors influencing variability (6). However, the clinical application of modelbased personalized vancomycin therapy is still limited. The objective of the present study was to evaluate the clinical utility and safety of a patient-tailored dose of vancomycin in neonates. Model-based patient-tailored dose of vancomycin. Special training was conducted in each NICU. We first informed the staff of the clinical pharmacology of vancomycin, its pharmacokinetic variability, and a large variation of dosage schedules currently used. We then explained the principles of individual dosage adaptation and how we developed the Excel dosing calculator using the results from our published population pharmacokinetic model (6). MATERIALS AND METHODS Neonates receiving vancomycin as a continuous infusion in one of threeIn order to calculate the patient-tailored dosing of vancomycin for each neonate, neonatologists had to enter four patient covariates in the calculator, including birth weight (in grams), current weight (in grams), postnatal age (PNA; in days), and serum creatinine concentration (in micromoles per liter) measured within 48 h of starting vancomycin treatment. The developed calculator was locked, and no other information was required. The patient-tailored dose is calculated automatically by using the following pharmacokinetic equations.Maintenance dose ϭ Target concentration ϫ CL ϫ 24 hwhere the loading dose is in milligrams, the maintenance dose is in milligrams per 24 h, the target concentration is in milligrams per liter, V (vol-

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Section: Discussionmentioning

confidence: 99%

Clinical Utility and Safety of a Model-Based Patient-Tailored Dose of Vancomycin in Neonates

Leroux

Jacqz-Aigrain

Biran

et al. 2016

Antimicrob Agents Chemother

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“…Over the past decades, the field of pharmacology has been evolving and modeling and simulation has started to play a role in improving pharmacotherapy in the pediatric population (7,29). In general, more efforts should be put in the design of pediatric studies, so that the obtained data are the most informative to answer the research question.…”

Section: Expert Commentarymentioning

confidence: 99%

“…In absence of results of dedicated pediatric studies, pediatric doses have been scaled from adult pharmacokinetic (PK) and pharmacodynamic (PD) data using different methods (6,7). These methods include empirical approaches (e.g.…”

Section: Pharmacotherapy In Clinical Practicementioning

confidence: 99%

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

Brussee

Calvier

Krekels

et al. 2016

Expert Review of Clinical Pharmacology

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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.

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“…In contrast, the FDA requires sponsors to provide a pediatric study plan by the end of phase 2 trials in adults. In both the US and European approaches, PK‐PD studies and modeling can support extrapolation of efficacy and dose selection, thereby streamlining and improving the accuracy of clinical trials (Figure ) …”

Section: Quantitative Information May Be Obtained From Trials In Adulmentioning

confidence: 99%

Developmental Pharmacodynamics and Modeling in Pediatric Drug Development

Conklin

Hoffman

Anker

2019

The Journal of Clinical Pharma

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Challenges in pediatric drug development include small patient numbers, limited outcomes research, ethical barriers, and sparse biosamples. Increasingly, pediatric drug development is focusing on extrapolation: leveraging knowledge about adult disease and drug responses to inform projections of drug and clinical trial performance in pediatric subpopulations. Pharmacokinetic‐pharmacodynamic (PK‐PD) modeling and extrapolation aim to reduce the numbers of patients and data points needed to establish efficacy. Planning for PK‐PD and biomarker studies should begin early in the adult drug development program. Extrapolation relies on the assumption that both the underlying disease and the mechanism of action of the drug used to treat that disease are similar in adults and pediatric subpopulations. Clearly, developmental changes in PK and PD need to be considered to enhance the quality of PK‐PD modeling and, therefore, increase the success of extrapolation. This article focuses on the influence of differences in PD between adults and pediatric subpopulations that are highly relevant for the use of extrapolation.

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A Survey of Neonatal Pharmacokinetic and Pharmacodynamic Studies in Pediatric Drug Development

Cited by 32 publications

References 13 publications

Clinical Utility and Safety of a Model-Based Patient-Tailored Dose of Vancomycin in Neonates

Clinical Utility and Safety of a Model-Based Patient-Tailored Dose of Vancomycin in Neonates

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

Developmental Pharmacodynamics and Modeling in Pediatric Drug Development

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