Individualized dosing regimens in children based on population PKPD modelling: Are we ready for it?

Knibbe, Catherijne A. J.; Danhof, Meindert

doi:10.1016/j.ijpharm.2011.02.056

Cited by 46 publications

(39 citation statements)

References 31 publications

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“…In order to facilitate the development of rational drug dosing schemes in the pediatric population, new approaches are (2)(3)(4)(5). At this moment, several pediatric pharmacokinetic models of vancomycin have been published (19-34, 36, 54-59), but only few individualized, model-based dosing algorithms are available (25,27,30,34,57,59).…”

Section: Discussionmentioning

confidence: 99%

“…While pediatric dosing regimens are mostly empirically derived using extrapolations based on body weight (2,3), it has been shown before that dosing in children should be guided by the understanding of developmental changes in the pharmacokinetic and/or pharmacodynamic relation of drugs (2,4,5). More specifically, translation of results from pharmacokinetic modeling studies has been shown to result in individualized dosing guidelines for many different drugs in pediatric clinical practice (5)(6)(7)(8)(9).…”

mentioning

confidence: 99%

“…Both models were based on a very large number of patients and internally validated (22,23). In order to further investigate the predictive performance of these models, an external validation procedure with external data sets is needed (2)(3)(4)(5). This external validation is necessary to allow the use of the model for deriving model-based dosing algorithms (3)(4)(5).…”

mentioning

confidence: 99%

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

Janssen

Välitalo

Allegaert

et al. 2016

Antimicrob Agents Chemother

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iBecause 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 (AUC 24 /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. In the pediatric population, drugs are often administered in an off-label or unlicensed manner (1). While pediatric dosing regimens are mostly empirically derived using extrapolations based on body weight (2, 3), it has been shown before that dosing in children should be guided by the understanding of developmental changes in the pharmacokinetic and/or pharmacodynamic relation of drugs (2, 4, 5). More specifically, translation of results from pharmacokinetic modeling studies has been shown to result in individualized dosing guidelines for many different drugs in pediatric clinical practice (5-9).The antibacterial agent vancomycin is commonly used to treat infections caused by Gram-positive organisms, like methicillinresistant Staphylococcus aureus (MRSA) and amoxicillin-resistant Enterococcus species, in both adults and pediatric patients (10). In neonates, MRSA infection is relatively rare, and coagulase-negative staphylococci are the most commonly identified infectious organisms necessitating vancomycin treatment (11,12). For vancomycin, it has been shown that bacterial killing of S. aureus is best predicted by the area under the concentration-time curve over 24 h (AUC 24 ) divided by the MIC for the infecting pathogen (AUC 24 / MIC) (13-15). In adult patients, an AUC 24 /MIC of Ն400 resulted in a superior clinical and...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Janssen

Välitalo

Allegaert

et al. 2016

Antimicrob Agents Chemother

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“…The incorporation of covariates into a PKPD or disease model has an important advantage in that it enhances the prediction of response for specific groups of patients [94][95][96]. In conjunction with clinical trial simulations, model-based techniques offer an excellent opportunity for the evaluation of novel therapies [97] as well as personalization of the dosing regimen for children [98].…”

Section: Understanding and Predicting Variabilitymentioning

confidence: 99%

Pharmacotherapy in pediatric epilepsy: from trial and error to rational drug and dose selection – a long way to go

Dijkman

Álvarez-Jiménez

Danhof

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Whereas ongoing efforts in epilepsy research focus on the underlying disease processes, the lack of a physiologically based rationale for drug and dose selection contributes to inadequate treatment response in children. In fact, limited information on the interindividual variation in pharmacokinetics and pharmacodynamics of anti-epileptic drugs (AEDs) in children drive prescription practice, which relies primarily on dose regimens according to a mg/kg basis. Such practice has evolved despite advancements in pediatric pharmacology showing that growth and maturation processes do not correlate linearly with changes in body size. Areas covered: In this review we aim to provide 1) a comprehensive overview of the sources of variability in the response to AEDs, 2) insight into novel methodologies to characterise such variation and 3) recommendations for treatment personalisation. Expert opinion: The use of pharmacokinetic-pharmacodynamic principles in clinical practice is hindered by the lack of biomarkers and by practical constraints in the evaluation of polytherapy. The identification of biomarkers and their validation as tools for drug development and therapeutics will require some time. Meanwhile, one should not miss the opportunity to integrate the available pharmacokinetic data with modeling and simulation concepts to prevent further delays in the development of personalised treatments for pediatric patients.

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“…Pediatric developmental changes must be taken into account, as they also play a key role in pharmacokinetics. For example, obvious maturation changes are related to the volume increase of luminal fluids, intestinal surface area, and intestinal permeability (12)(13)(14)(15). Administered dose is also fundamentally important, and therefore, there may be a need for a more quantitative, dose-dependent approach to pediatric BCS (16,17).…”

Section: Challenges In the Development Of Pediatric Dosage Forms Frommentioning

confidence: 99%

A Report from the Pediatric Formulations Task Force: Perspectives on the State of Child-Friendly Oral Dosage Forms

Zajicek

Fossler

Barrett

et al. 2013

AAPS J

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Abstract. Despite the fact that a significant percentage of the population is unable to swallow tablets and capsules, these dosage forms continue to be the default standard. These oral formulations fail many patients, especially children, because of large tablet or capsule size, poor palatability, and lack of correct dosage strength. The clinical result is often lack of adherence and therapeutic failure. The American Association of Pharmaceutical Scientists formed a Pediatric Formulations Task Force, consisting of members with various areas of expertise including pediatrics, formulation development, clinical pharmacology, and regulatory science, in order to identify pediatric, manufacturing, and regulatory issues and areas of needed research and regulatory guidance. Dosage form and palatability standards for all pediatric ages, relative bioavailability requirements, and small batch manufacturing capabilities and creation of a viable economic model were identified as particular needs. This assessment is considered an important first step for a task force seeking creative approaches to providing more appropriate oral formulations for children.

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Individualized dosing regimens in children based on population PKPD modelling: Are we ready for it?

Cited by 46 publications

References 31 publications

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

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

Pharmacotherapy in pediatric epilepsy: from trial and error to rational drug and dose selection – a long way to go

A Report from the Pediatric Formulations Task Force: Perspectives on the State of Child-Friendly Oral Dosage Forms

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