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Research ArticleSpecial Section on Pediatric Drug Disposition and Pharmacokinetics

Predicting Stereoselective Disposition of Carvedilol in Adult and Pediatric Chronic Heart Failure Patients by Incorporating Pathophysiological Changes in Organ Blood Flows–A Physiologically Based Pharmacokinetic Approach

Muhammad Fawad Rasool, Feras Khalil and Stephanie Läer
Drug Metabolism and Disposition July 2016, 44 (7) 1103-1115; DOI: https://doi.org/10.1124/dmd.115.068858
Muhammad Fawad Rasool
Department of Clinical Pharmacy and Pharmacotherapy, Heinrich-Heine University, Düsseldorf, Germany (M.F.R., F.K., S.L.); and Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan (M.F.R.)
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Feras Khalil
Department of Clinical Pharmacy and Pharmacotherapy, Heinrich-Heine University, Düsseldorf, Germany (M.F.R., F.K., S.L.); and Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan (M.F.R.)
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Stephanie Läer
Department of Clinical Pharmacy and Pharmacotherapy, Heinrich-Heine University, Düsseldorf, Germany (M.F.R., F.K., S.L.); and Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan (M.F.R.)
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Abstract

Chronic heart failure (CHF) is a systemic low perfusion syndrome resulting from impairment in the pumping function of the heart. The decrease in blood supply to body organs can potentially affect the pharmacokinetics (PK) of the drugs being administered. Carvedilol is administered as a racemic mixture and undergoes extensive stereoselective first pass metabolism. For such a drug, the pathophysiological changes occurring in CHF can have a profound impact on PK, and thus the resulting pharmacodynamic response, of both enantiomers. The aim of the current work was to predict stereoselective disposition of carvedilol after incorporating the pathophysiological changes in CHF into a whole-body physiologically based PK model using Simcyp, and to scale that model to pediatric CHF patients on a physiologic basis to investigate whether the same changes in the adult model can also be adopted for children. The developed model has successfully described PK of carvedilol enantiomers in healthy adults and in patients after the incorporation of reduced organ blood flows, as seen by the visual predictive checks and the calculated observed/predicted ratios for all PK parameters of interest. In contrast to adults, pediatric patients up to 12 years of age were better described without the reductions in organ blood flow, whereas older pediatric patients were better described after incorporating organ blood flow reductions. These findings indicate that the incorporated blood flow reductions in the adult model cannot be directly adopted in pediatrics, at least for the young ones; however, to draw definite conclusions, more data are still needed.

Footnotes

    • Received December 8, 2015.
    • Accepted April 7, 2016.
  • This work was supported by the European Union Seventh Framework Programme (FP7/2007-2013) under Grant Agreement 602295 LENA.

  • dx.doi.org/10.1124/dmd.115.068858.

  • ↵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

Predicting Stereoselective PK of Carvedilol–A PBPK Approach

Muhammad Fawad Rasool, Feras Khalil and Stephanie Läer
Drug Metabolism and Disposition July 1, 2016, 44 (7) 1103-1115; DOI: https://doi.org/10.1124/dmd.115.068858

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Research ArticleSpecial Section on Pediatric Drug Disposition and Pharmacokinetics

Predicting Stereoselective PK of Carvedilol–A PBPK Approach

Muhammad Fawad Rasool, Feras Khalil and Stephanie Läer
Drug Metabolism and Disposition July 1, 2016, 44 (7) 1103-1115; DOI: https://doi.org/10.1124/dmd.115.068858
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