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A Mechanistic Approach for the Scaling of Clearance in Children

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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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Acknowledgements

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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Authors and Affiliations

  1. Competence Center Systems Biology, Bayer Technology Services GmbH, Bldg E41, Leverkusen, 51368, Germany

    Andrea N. Edginton, Walter Schmitt & Stefan Willmann

  2. Department for Clinical Pharmacokinetics, Bayer HealthCare AG, Wuppertal, Germany

    Barbara Voith

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  1. Andrea N. Edginton
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  2. Walter Schmitt
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  4. Stefan Willmann
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Correspondence to Andrea N. Edginton.

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Edginton, A.N., Schmitt, W., Voith, B. et al. A Mechanistic Approach for the Scaling of Clearance in Children. Clin Pharmacokinet 45, 683–704 (2006). https://doi.org/10.2165/00003088-200645070-00004

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