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Prediction of Clinical Transporter Mediated Drug‐Drug Interactions via Co‐measurement of Pitavastatin and Eltrombopag in Human Hepatocyte Models

Carter, SJ; Chouhan, B; Sharma, P; Chappell, MJ; (2020) Prediction of Clinical Transporter Mediated Drug‐Drug Interactions via Co‐measurement of Pitavastatin and Eltrombopag in Human Hepatocyte Models. CPT: Pharmacometrics & Systems Pharmacology , 9 pp. 211-221. 10.1002/psp4.12505. Green open access

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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 co‐measurement 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 to eltrombopag. A semi‐mechanistic PBPK model was developed to evaluate the potential for clinical drug‐drug interactions. The PBPK model predicted a two fold increase in the pitavastatin Cmax and AUC 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 semi‐mechanistic PBPK model gave more informed predictions of transporter mediated drug‐drug interactions.

Type: Article
Title: Prediction of Clinical Transporter Mediated Drug‐Drug Interactions via Co‐measurement of Pitavastatin and Eltrombopag in Human Hepatocyte Models
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/psp4.12505
Publisher version: https://doi.org/10.1002/psp4.12505
Language: English
Additional information: Copyright © 2020 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: In Vitro, Mathematical Modeling, Physiologically‐based pharmacokinetics, Inhibition, Drug Transport, Drug‐Drug Interactions
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10093636
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