Prediction of Clinical Transporter-Mediated Drug-Drug Interactions via Comeasurement of Pitavastatin and Eltrombopag in Human Hepatocyte Models.

CPT: Pharmacometrics & Systems Pharmacology
Simon J CarterMichael J Chappell

Abstract

A structurally identifiable micro-rate constant mechanistic model was used to describe the interaction between pitavastatin and eltrombopag, with improved goodness-of-fit values through comeasurement of pitavastatin and eltrombopag. Transporter association and dissociation rate constants and passive rates out of the cell were similar between pitavastatin and eltrombopag. Translocation into the cell through transporter-mediated uptake was six times greater for pitavastatin, leading to pronounced inhibition of pitavastatin uptake by eltrombopag. The passive rate into the cell was 91 times smaller for pitavastatin compared with eltrombopag. A semimechanistic physiologically-based pharmacokinetic (PBPK) model was developed to evaluate the potential for clinical drug-drug interactions (DDIs). The PBPK model predicted a twofold increase in the pitavastatin peak blood concentration and area under the concentration-time curve in the presence of eltrombopag in simulated healthy volunteers. The use of structural identifiability supporting experimental design combined with robust micro-rate constant parameter estimates and a semimechanistic PBPK model gave more informed predictions of transporter-mediated DDIs.

References

Jan 1, 1996·Critical Reviews in Oral Biology and Medicine : an Official Publication of the American Association of Oral Biologists·J A Garlick, E S Fenjves
Aug 7, 2002·Clinical Pharmacokinetics·Michael S RobertsMichael Weiss
Nov 5, 2003·Critical Reviews in Toxicology·Paul S PriceDouglas R Tedder
Apr 6, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Masaru HiranoYuichi Sugiyama
Aug 26, 2006·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Anna-Karin Sohlenius-Sternbeck
Apr 23, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Stuart W PaineRobert J Riley
Oct 31, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Takao WatanabeYuichi Sugiyama
Mar 23, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Kazuya TakeuchiYukio Kato
Mar 26, 2011·British Journal of Clinical Pharmacology·Alicia J AllredEdmund Lee
Jun 8, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yanli DengPeter D Gorycki
May 23, 2012·Mathematical Biosciences·Milena AnguelovaMats Jirstrand
Jun 6, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Karelle MénochetAleksandra Galetin
Dec 12, 2012·Computer Methods and Programs in Biomedicine·Daniel J BearupMichael J Chappell
Jan 21, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Kazuya TakeuchiYukio Kato
Mar 13, 2014·British Journal of Clinical Pharmacology·Thomayant PrueksaritanontS Aubrey Stoch
Jul 17, 2014·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Thomas R B GrandjeanCharles J O'Donnell
Jun 18, 2015·Current Therapeutic Research, Clinical and Experimental·Zhu LuoYing Wang
Dec 29, 2016·CPT: Pharmacometrics & Systems Pharmacology·B GuiastrennecM Bergstrand
May 5, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Takashi YoshikadoYuichi Sugiyama

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