Incorporation of the Time-Varying Postprandial Increase in Splanchnic Blood Flow into a PBPK Model to Predict the Effect of Food on the Pharmacokinetics of Orally Administered High-Extraction Drugs

The AAPS Journal
Rachel RoseMasoud Jamei

Abstract

Following a meal, a transient increase in splanchnic blood flow occurs that can result in increased exposure to orally administered high-extraction drugs. Typically, physiologically based pharmacokinetic (PBPK) models have incorporated this increase in blood flow as a time-invariant fed/fasted ratio, but this approach is unable to explain the extent of increased drug exposure. A model for the time-varying increase in splanchnic blood flow following a moderate- to high-calorie meal (TV-Q Splanch) was developed to describe the observed data for healthy individuals. This was integrated within a PBPK model and used to predict the contribution of increased splanchnic blood flow to the observed food effect for two orally administered high-extraction drugs, propranolol and ibrutinib. The model predicted geometric mean fed/fasted AUC and C max ratios of 1.24 and 1.29 for propranolol, which were within the range of published values (within 1.0-1.8-fold of values from eight clinical studies). For ibrutinib, the predicted geometric mean fed/fasted AUC and C max ratios were 2.0 and 1.84, respectively, which was within 1.1-fold of the reported fed/fasted AUC ratio but underestimated the reported C max ratio by up to 1.9-fold. For both drugs...Continue Reading

References

Mar 1, 1979·Clinical Pharmacokinetics·P A Routledge, D G Shand
Jul 1, 1978·Clinical Pharmacology and Therapeutics·A J McLeanD Lalka
Jul 1, 1977·Clinical Pharmacology and Therapeutics·A MelanderE Wåhlin
Nov 1, 1992·Acta Physiologica Scandinavica·B A Waaler, M Eriksen
May 1, 1992·Clinical Pharmacology and Therapeutics·P M ColangeloP J Wedlund
Jan 1, 1990·European Journal of Clinical Pharmacology·H LiedholmA Melander
Jan 1, 1989·European Journal of Clinical Pharmacology·L A BauerJ Olsen
Apr 1, 1989·British Journal of Clinical Pharmacology·P ColangeloP McNamara
Jan 1, 1988·Scandinavian Journal of Gastroenterology·M I Qamar, A E Read
Nov 1, 1987·Journal of Clinical Pharmacology·G CheymolJ Dry
Oct 1, 1986·Clinical Pharmacology and Therapeutics·L S OlanoffE C Conradi
May 1, 1981·British Journal of Clinical Pharmacology·T K DaneshmendC J Roberts
Nov 1, 1984·British Journal of Clinical Pharmacology·T WalleT E Gaffney
Dec 1, 1983·British Journal of Clinical Pharmacology·I H BenedekP J McNamara
Jan 1, 1984·European Journal of Clinical Pharmacology·R BendayanG J Caranasos
Sep 1, 1983·Clinical Pharmacology and Therapeutics·C K SvenssonD Lalka
Jul 1, 1981·Clinical Pharmacology and Therapeutics·A J McLeanF J Dudley
Oct 1, 1981·British Journal of Clinical Pharmacology·E A Taylor, P Turner
Dec 1, 1981·Clinical Pharmacology and Therapeutics·T WalleT E Gaffney
Jun 1, 1994·The British Journal of Nutrition·M B Sidery, I A Macdonald
Jan 1, 1994·European Journal of Applied Physiology and Occupational Physiology·M DauzatG Pomier-Layrargues
Jan 1, 1996·Annual Review of Nutrition·P G Welling
Jun 1, 1997·British Journal of Clinical Pharmacology·G CheymolE Snoeck
Mar 10, 2000·Journal of Clinical Pharmacology·M D KarolJ H Cavanaugh
Aug 18, 2000·The Journal of Surgical Research·P J MathesonR N Garrison
Jul 16, 2003·International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity·K N FraynS W Coppack
Feb 27, 2004·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·N J ProctorA Rostami-Hodjegan
Apr 29, 2005·Journal of Pharmaceutical Sciences·Trudy RodgersMalcolm Rowland
Dec 24, 2005·Scandinavian Journal of Gastroenterology·Jan L MadsenSøren Møller
Jun 10, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Taina StenMoshe Finel
Jun 14, 2006·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·E M HowgateA Rostami-Hodjegan
Sep 28, 2006·The Journal of Clinical Endocrinology and Metabolism·George DimitriadisSotirios A Raptis
Apr 26, 2007·World Journal of Gastroenterology : WJG·Adam David JeaysDavid Rodney Hose
Nov 6, 2007·Current Drug Metabolism·Jiansong YangAmin Rostami-Hodjegan

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Citations

Aug 3, 2018·CPT: Pharmacometrics & Systems Pharmacology·Benjamin GuiastrennecMats O Karlsson
Apr 10, 2020·Journal of Veterinary Pharmacology and Therapeutics·Zhoumeng LinJim E Riviere
Sep 28, 2020·The AAPS Journal·Jingcheng XiaoPeng Zou
Jun 16, 2018·Journal of Pharmaceutical Sciences·Christophe TistaertFilippos Kesisoglou

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Methods Mentioned

BETA
SMA

Software Mentioned

Q Splanch
Simcyp
Simcyp Simulator
TV

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