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Clinical Pharmacokinetics

Erschienen in:

01.07.2006 | Original Research Article

A Mechanistic Approach for the Scaling of Clearance in Children

verfasst von: Dr Andrea N. Edginton, Walter Schmitt, Barbara Voith, Stefan Willmann

Erschienen in: Clinical Pharmacokinetics | Ausgabe 7/2006

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Abstract

Background and objective

Clearance is an important pharmacokinetic concept for scaling dosage, understanding the risks of drug-drug interactions and environmental risk assessment in children. Accurate clearance scaling to children requires prior knowledge of adult clearance mechanisms and the age-dependence of physiological and enzymatic development. The objective of this research was to develop and evaluate ontogeny models that would provide an assessment of the age-dependence of clearance.

Methods

Using in vitro data and/or in vivo clearance values for children for eight compounds that are eliminated primarily by one process, models for the ontogeny of renal clearance, cytochrome P450 (CYP) 3A4, CYP2E1, CYP1A2, uridine diphosphate glucuronosyltransferase (UGT) 2B7, UGT1A6, sulfonation and biliary clearance were developed. Resulting ontogeny models were evaluated using six compounds that demonstrated elimination via multiple pathways. The proportion of total clearance attributed to each clearance pathway in adults was delineated. Each pathway was individually scaled to the desired age, inclusive of protein-binding prediction, and summed to generate a total plasma clearance for the child under investigation. The paediatric age range included in the study was premature neonates to sub-adults.

Results

There was excellent correlation between observed and predicted clearances for the model development (R² = 0.979) and test sets (Q² = 0.927). Clearance in premature neonates could also be well predicted (development R² = 0.951; test Q² = 0.899).

Conclusion

Paediatric clinical trial development could greatly benefit from clearance scaling, particularly in guiding dosing regimens. Furthermore, since the proportion of clearance via different elimination pathways is age-dependent, information could be gained on the developmental extent of drug-drug interactions.

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Titel: A Mechanistic Approach for the Scaling of Clearance in Children
verfasst von: Dr Andrea N. Edginton
Walter Schmitt
Barbara Voith
Stefan Willmann
Publikationsdatum: 01.07.2006
Verlag: Springer International Publishing
Erschienen in: Clinical Pharmacokinetics / Ausgabe 7/2006
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926
DOI: https://doi.org/10.2165/00003088-200645070-00004

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

A Mechanistic Approach for the Scaling of Clearance in Children

Abstract

Background and objective

Methods

Results

Conclusion

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Abstract

Background and objective

Methods

Results

Conclusion

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