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Research ArticleArticle

How does the In Vivo Biliary Elimination of Drugs Change with Age? Evidence from In Vitro and Clinical Data Using a Systems Pharmacology Approach

Trevor N Johnson, Masoud Jamei and Karen Rowland-Yeo
Drug Metabolism and Disposition February 9, 2016, dmd.115.068643; DOI: https://doi.org/10.1124/dmd.115.068643
Trevor N Johnson
1 Simcyp Limited (a Certara Company);
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  • For correspondence: trevor.johnson@certara.com
Masoud Jamei
2 Simcyp Limited (A Certara Company)
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Karen Rowland-Yeo
2 Simcyp Limited (A Certara Company)
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Abstract

Information on the developmental changes of biliary excretion (BE) of drugs is sparse. The aims of this study were to collate literature data on the pharmacokinetics of biliary excreted drugs used in pediatrics and to apply a Physiologically Based Pharmacokinetic (PBPK) model to predict their systemic clearance (CL) with a view to elucidating age-related changes of biliary excretion. Drug parameters for azithromycin, ceftriaxone, digoxin administered intravenously (IV) and buprenorphine (IV and sublingual) were collated from the literature and used in the Simcyp Simulator to predict adult CL values which were then validated against observed data. The change in CL with age was simulated in the pediatric model and compared to observed data; where necessary, the ontogeny function associated with BE was applied to recover the age-related CL. For azithromycin a fraction of adult BE activity of 15% was necessary to predict the CL in neonates (26 weeks GA) whilst 100% activity was apparent by 7 months. For ceftriaxone and digoxin full BE activity appeared to be present at term birth, for the latter an adult BE activity of 10% was needed to predict the CL in premature neonates (30 weeks GA). The CL of buprenorphine with age was described by the ontogeny of the major elimination pathways (CYP3A4 and UGT1A1) with no ontogeny assumed for the biliary component. Thus, the ontogeny of BE for all four drugs appears to be rapid and attain adult levels at birth or within the first few months of postnatal age.

  • biliary excretion
  • ontogeny/development/ageing
  • physiologically-based pharmacokinetic modeling/PBPK
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 49 (5)
Drug Metabolism and Disposition
Vol. 49, Issue 5
1 May 2021
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Research ArticleArticle

How does the In Vivo Biliary Elimination of Drugs Change with Age? Evidence from In Vitro and Clinical Data Using a Systems Pharmacology Approach

Trevor N Johnson, Masoud Jamei and Karen Rowland-Yeo
Drug Metabolism and Disposition February 9, 2016, dmd.115.068643; DOI: https://doi.org/10.1124/dmd.115.068643

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Research ArticleArticle

How does the In Vivo Biliary Elimination of Drugs Change with Age? Evidence from In Vitro and Clinical Data Using a Systems Pharmacology Approach

Trevor N Johnson, Masoud Jamei and Karen Rowland-Yeo
Drug Metabolism and Disposition February 9, 2016, dmd.115.068643; DOI: https://doi.org/10.1124/dmd.115.068643
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