Leiden University Scholarly Publications

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Calvier, E.A.M. (2018)

How to scale clearance from adults to children for drugs undergoing hepatic metabolism? Insights from advanced PBPK modelling and simulation

Doctoral Thesis
The aim of this thesis is to expedite and ensure the systematic accuracy of clearance scaling from adults to paediatric patients, with a special focus on drugs undergoing hepatic metabolism. A physiologically-based pharmacokinetic simulation workflow was developed to unravel the conditions for accurate scaling of drug clearance from adults to children as young as term neonates of one day for various methods. This disproved the belief that a universal allometric exponent can scale size-related changes in clearance across the paediatric age range, and showed that isoenzyme maturation and drug properties, especially extraction ratio and drug binding to alpha-1-acid glycoprotein, should be accounted for when scaling clearance to young children. Based on these results, a clearance scaling decision tree is proposed, which allows pharmacologists for the first-time to select scaling method(s) that require a minimum but still sufficient amount of information to accurately scale clearance...Show moreThe aim of this thesis is to expedite and ensure the systematic accuracy of clearance scaling from adults to paediatric patients, with a special focus on drugs undergoing hepatic metabolism. A physiologically-based pharmacokinetic simulation workflow was developed to unravel the conditions for accurate scaling of drug clearance from adults to children as young as term neonates of one day for various methods. This disproved the belief that a universal allometric exponent can scale size-related changes in clearance across the paediatric age range, and showed that isoenzyme maturation and drug properties, especially extraction ratio and drug binding to alpha-1-acid glycoprotein, should be accounted for when scaling clearance to young children. Based on these results, a clearance scaling decision tree is proposed, which allows pharmacologists for the first-time to select scaling method(s) that require a minimum but still sufficient amount of information to accurately scale clearance of drugs with known properties to a desired paediatric age-range. Moreover, an analysis framework is provided to assess the feasibility and clinical trial requirements for the estimation of PBPK parameters using population pharmacokinetic modelling, which has the potential to expedite development of PBPK models for understudied paediatric subpopulations.Show less
Paediatrics
Clearance
Allometric scaling
Hepatic metabolism
Physiologically-based pharmacokinetics
Pharmacokinetics
Optimal design
All authors
Calvier, E.A.M.
Supervisor
Knibbe, C.A.J.; Tibboel, D.
Co-supervisor
Krekels, E.H.J.
Committee
Irth, H.; Bouwstra, J.A.; Graaf, P.H. van der; Guchelaar, H.J.; Vermeulen, A.; Vinks, A.A.
Qualification
Doctor (dr.)
Awarding Institution
Division Systems Biomedicine and Pharmacology/LACDR, Science, Leiden University
Date
2018-12-19
ISBN (print)
9789463324373