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Research ArticleSpecial Section on Pediatric Drug Disposition and Pharmacokinetics

Considering Age Variation When Coining Drugs as High versus Low Hepatic Extraction Ratio

Farzaneh Salem, Khaled Abduljalil, Yoshiteru Kamiyama and Amin Rostami-Hodjegan
Drug Metabolism and Disposition July 2016, 44 (7) 1099-1102; DOI: https://doi.org/10.1124/dmd.115.067595
Farzaneh Salem
Simcyp Limited (a Certara Company), Sheffield, United Kingdom (F.S., K.A., A.R.H.); Analysis & Pharmacokinetics Laboratories, Astellas Pharma Inc., Ibaraki, Japan (Y.K.); Centre for Applied Pharmaceutical Research, Manchester Pharmacy School, University of Manchester, Manchester, United Kingdom (Y.K., A.R.H.)
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Khaled Abduljalil
Simcyp Limited (a Certara Company), Sheffield, United Kingdom (F.S., K.A., A.R.H.); Analysis & Pharmacokinetics Laboratories, Astellas Pharma Inc., Ibaraki, Japan (Y.K.); Centre for Applied Pharmaceutical Research, Manchester Pharmacy School, University of Manchester, Manchester, United Kingdom (Y.K., A.R.H.)
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Yoshiteru Kamiyama
Simcyp Limited (a Certara Company), Sheffield, United Kingdom (F.S., K.A., A.R.H.); Analysis & Pharmacokinetics Laboratories, Astellas Pharma Inc., Ibaraki, Japan (Y.K.); Centre for Applied Pharmaceutical Research, Manchester Pharmacy School, University of Manchester, Manchester, United Kingdom (Y.K., A.R.H.)
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Amin Rostami-Hodjegan
Simcyp Limited (a Certara Company), Sheffield, United Kingdom (F.S., K.A., A.R.H.); Analysis & Pharmacokinetics Laboratories, Astellas Pharma Inc., Ibaraki, Japan (Y.K.); Centre for Applied Pharmaceutical Research, Manchester Pharmacy School, University of Manchester, Manchester, United Kingdom (Y.K., A.R.H.)
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Abstract

The hepatic extraction ratio (EH) is commonly considered an “inherent attribute” of drug. It determines the main physiological and biological elements of the system (patient attributes) that are most significant in interindividual variability of clearance. The EH consists of three age-dependent parameters: fraction of unbound drug in blood (fu.B), hepatic intrinsic clearance of unbound drug (CLu.int,H), and hepatic blood flow (QH). When the age-effects on these elements are not proportional, a given drug may shift from so-called high extraction status to low extraction. To demonstrate the impact of age-related changes on fu.B, CLu.int,H, and QH, the EH of midazolam and two hypothetical drugs with 10-fold higher and 10-fold lower CLu.int,H than midazolam were investigated in pediatrics based on known ontogeny functions. The EH was simulated using Simcyp software, version 14. This was then complemented by a comprehensive literature survey to identify the commonly applied covariates in pediatric population pharmacokinetic (PopPK) studies. Midazolam EH decreased from 0.6 in adults to 0.02 at birth, making its clearance much more susceptible to changes in CLu.int,H and fu.B than in adults and reducing the impact of QH on clearance. The drug with 10-fold higher CLu.int,H was categorized as high extraction from 4 days old onward whereas the drug with 10-fold lower CLu.int,H remained low extraction from birth to adulthood. Approximately 50% of collected PopPK studies (n = 120) did not consider interaction between age and other covariates. Interaction between covariates and age should be considered as part of studies involving younger pediatric patients. The EH cannot be considered an inherent drug property without considering the effect of age.

Footnotes

    • Received October 1, 2015.
    • Accepted February 9, 2016.
  • dx.doi.org/10.1124/dmd.115.067595.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (7)
Drug Metabolism and Disposition
Vol. 44, Issue 7
1 Jul 2016
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Research ArticleSpecial Section on Pediatric Drug Disposition and Pharmacokinetics

Consequences of Age Variation in Hepatic Extraction Ratios

Farzaneh Salem, Khaled Abduljalil, Yoshiteru Kamiyama and Amin Rostami-Hodjegan
Drug Metabolism and Disposition July 1, 2016, 44 (7) 1099-1102; DOI: https://doi.org/10.1124/dmd.115.067595

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Research ArticleSpecial Section on Pediatric Drug Disposition and Pharmacokinetics

Consequences of Age Variation in Hepatic Extraction Ratios

Farzaneh Salem, Khaled Abduljalil, Yoshiteru Kamiyama and Amin Rostami-Hodjegan
Drug Metabolism and Disposition July 1, 2016, 44 (7) 1099-1102; DOI: https://doi.org/10.1124/dmd.115.067595
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