Clinical Pharmacokinetics

, Volume 45, Issue 7, pp 683–704 | Cite as

A Mechanistic Approach for the Scaling of Clearance in Children

  • Andrea N. EdgintonEmail author
  • Walter Schmitt
  • Barbara Voith
  • Stefan Willmann
Original Research Article


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.


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.


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).


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.


Glomerular Filtration Rate Ropivacaine Alfentanil Total Clearance Unbind Fraction 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors acknowledge valuable discussions with the colleagues from the Clinical Pharmacokinetics Department of Bayer HealthCare AG, particularly Dr Gertrud Ahr and Dr Heino Stass.

No sources of funding were used to assist in the preparation of this study. The authors have no conflicts of interest that are directly relevant to the content of this study.


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Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  • Andrea N. Edginton
    • 1
    Email author
  • Walter Schmitt
    • 1
  • Barbara Voith
    • 2
  • Stefan Willmann
    • 1
  1. 1.Competence Center Systems BiologyBayer Technology Services GmbHLeverkusenGermany
  2. 2.Department for Clinical PharmacokineticsBayer HealthCare AGWuppertalGermany

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