A Mechanistic Approach for the Scaling of Clearance in Children

Edginton, Andrea N.; Schmitt, Walter; Voith, Barbara; Willmann, Stefan

doi:10.2165/00003088-200645070-00004

Cited by 195 publications

(206 citation statements)

References 176 publications

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“…The GFR (child) was calculated using a postmenstrual age model,31 and f u(child) was estimated using an age‐specific model considering plasma protein concentrations in children and the affinity of drugs for binding proteins 30, 32. Reabsorption (GFR fraction) was assumed to have no ontogeny.…”

Section: Methodsmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO

Watt

Cohen‐Wolkowiez

Barrett

et al. 2018

CPT Pharmacom & Syst Pharma

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Extracorporeal life support (e.g., dialysis, extracorporeal membrane oxygenation (ECMO)) can affect drug disposition, placing patients at risk for therapeutic failure. In this population, dose selection to achieve safe and effective drug exposure is difficult. We developed a novel and flexible approach that uses physiologically based pharmacokinetic (PBPK) modeling to translate results from ECMO ex vivo experiments into bedside dosing recommendations. To determine fluconazole dosing in children on ECMO, we developed a PBPK model, which was validated using fluconazole pharmacokinetic (PK) data in adults and critically ill infants. Next, an ECMO compartment was added to the PBPK model and parameterized using data from a previously published ex vivo study. Simulations using the final ECMO PBPK model reasonably characterized observed PK data in infants on ECMO, and the model was used to derive dosing in children on ECMO across the pediatric age spectrum. This approach can be generalized to other forms of extracorporeal life support (ECLS), such as dialysis.

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Section: Methodsmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO

Watt

Cohen‐Wolkowiez

Barrett

et al. 2018

CPT Pharmacom & Syst Pharma

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“…At present no specific information about ontogeny in humans is available for UGT2B15, whereas some information is available on other UGT isoforms, such as UGT1A1, the activity of which is low at birth, reaching levels comparable to adulthood within 3-6 months later (de Wildt et al, 1999), or UGT2B7 whose activity in neonates at term is only 5% that of adults, increases to 30% by 3 months of age, and reaches adult levels by 1 year of age (Edginton et al, 2006). This pattern is the one which has been used in human PBPK models to account for possible limited UGT activity for BPA conjugation during early life (Edginton and Ritter, 2009;Mielke and Gundert-Remy, 2009).…”

Section: The Enzymes Involved In Bpa Biotransformationmentioning

confidence: 99%

Scientific Opinion on Bisphenol A: evaluation of a study investigating its neurodevelopmental toxicity, review of recent scientific literature on its toxicity and advice on the Danish risk assessment of Bisphenol A

Flavourings¹

2010

EFSA Journal

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Bisphenol A (BPA) is used in the manufacture of plastics, to produce reusable drinking bottles, infant feeding bottles and other food storage containers. EFSA was asked to evaluate a dietary developmental neurotoxicity study in rats (Stump, 2009) and recent scientific literature (2007)(2008)(2009)(2010) in terms of relevance for the risk assessment of BPA. The impact of these studies on the current Tolerable Daily Intake (TDI) of 0.05 mg BPA/kg body weight (b.w.)/day as set by EFSA in 2006 was assessed. Advice on the Danish risk assessment underlying the Danish ban of BPA in food contact materials for infants aged 0-3 years is included. Overall, based on this comprehensive evaluation of recent toxicity data, the Panel on food contact materials, enzymes, flavourings and processing aids (CEF) concluded that no new study could be identified, which would call for a revision of the current TDI. This TDI is based on the No-Observed-Adverse-Effect-Level (NOAEL) of 5 mg/kg b.w./day from a multi-generation reproductive toxicity study in rats, and the application of an uncertainty factor of 100. This factor is regarded as conservative based on all information on BPA toxicokinetics. The Panel noted that some studies conducted on developing animals have suggested other BPA-related effects of possible toxicological relevance, in particular biochemical changes in brain, immune-modulatory effects and enhanced susceptibility to breast tumours. These studies had several shortcomings. At present the relevance of these findings for human health cannot be assessed. Should any new relevant data become available in the future, the Panel will reconsider this opinion. A minority opinion is expressed by a Panel member and presented in an Annex to this opinion. © European Food Safety Authority, 2010 KEY WORDSBisphenol A, BPA, CAS No. 00080-05-7, developmental toxicity, neurobehaviour, low dose effects. In order to provide a global view on the risk assessment of Bisphenol A, the CEF Panel decided to address the three mandates as given above in a single opinion and postponed the adoption of this comprehensive document to 23 rd September 2010.The three different questions raised by the Commission are dealt with in three different parts (PARTS I to III) of the opinion. PART IV presents an overview of the conclusions from PARTS I to III, together with an overall conclusion. PART IThe GLP compliant study by Stump (2009) was performed according to OECD guideline 426 to address any uncertainty regarding potential neurodevelopmental effects of BPA. BPA was administered daily in the diet at concentrations of 0, 0.15, 1.5, 75, 750, and 2250 mg/kg feed to female Sprague-Dawley rats from gestational day (GD) 0 to postnatal day (PND) 21. The relative estimated intakes (in mg/kg b.w./day) were 0, 0.01, 0.12, 5.85, 56.4 and 164 during gestation and 0, 0.03, 0.25, 13.1, 129 and 410 during lactation. The CEF Panel considers this treatment schedule as relevant to human exposure in utero and via either breastfeeding or infant bottle feeding (in this...

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“…Nonetheless, it is important to note that modelling of renal drug disposition in paediatrics requires special consideration to account for the maturation of renal function and ontogeny of protein expression. For those interested in this topic, modelling efforts and reviews have previously been reported (7)(8)(9). Another topic outside the scope of the current review is research into renal disposition in preclinical species.…”

Section: Introductionmentioning

confidence: 99%

Key to Opening Kidney for In Vitro-In Vivo Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and In Vitro-In Vivo Extrapolation

Scotcher

Jones²,

Posada

et al. 2016

AAPS J

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Abstract.It is envisaged that application of mechanistic models will improve prediction of changes in renal disposition due to drug-drug interactions, genetic polymorphism in enzymes and transporters and/or renal impairment. However, developing and validating mechanistic kidney models is challenging due to the number of processes that may occur (filtration, secretion, reabsorption and metabolism) in this complex organ. Prediction of human renal drug disposition from preclinical species may be hampered by species differences in the expression and activity of drug metabolising enzymes and transporters. A proposed solution is bottom-up prediction of pharmacokinetic parameters based on in vitro-in vivo extrapolation (IVIVE), mediated by recent advances in in vitro experimental techniques and application of relevant scaling factors. This review is a follow-up to the Part I of the report from the 2015 AAPS Annual Meeting and Exhibition (Orlando, FL; 25th-29th October 2015) which focuses on IVIVE and mechanistic prediction of renal drug disposition. It describes the various mechanistic kidney models that may be used to investigate renal drug disposition. Particular attention is given to efforts that have attempted to incorporate elements of IVIVE. In addition, the use of mechanistic models in prediction of renal drugdrug interactions and potential for application in determining suitable adjustment of dose in kidney disease are discussed. The need for suitable clinical pharmacokinetics data for the purposes of delineating mechanistic aspects of kidney models in various scenarios is highlighted.KEY WORDS: active renal excretion; human kidney transporters; human renal drug clearance; kidney disease; non-hepatic drug metabolism.

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A Mechanistic Approach for the Scaling of Clearance in Children

Cited by 195 publications

References 176 publications

Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO

Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO

Scientific Opinion on Bisphenol A: evaluation of a study investigating its neurodevelopmental toxicity, review of recent scientific literature on its toxicity and advice on the Danish risk assessment of Bisphenol A

Key to Opening Kidney for In Vitro-In Vivo Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and In Vitro-In Vivo Extrapolation

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