Carter, Simon J., Chouhan, Bhavik, Sharma, Pradeep and Chappell, Michael J. (2020) Prediction of clinical transporter‐mediated drug–drug interactions via comeasurement of pitavastatin and eltrombopag in human hepatocyte Models. CPT: pharmacometrics & systems pharmacology, 9 (4). pp. 211-221. doi:10.1002/psp4.12505 ISSN 2163-8306.
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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 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.
| Item Type: | Journal Article |
|---|---|
| Subjects: | R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Faculty of Science, Engineering and Medicine > Engineering > Engineering |
| Library of Congress Subject Headings (LCSH): | Drug interactions , Pharmacokinetics , Drugs -- Metabolism -- Evaluation |
| Journal or Publication Title: | CPT: pharmacometrics & systems pharmacology |
| Publisher: | Wiley-Blackwell Publishing Ltd. |
| ISSN: | 2163-8306 |
| Official Date: | April 2020 |
| Dates: | Date Event April 2020 Published 6 March 2020 Available 27 January 2020 Accepted |
| Volume: | 9 |
| Number: | 4 |
| Page Range: | pp. 211-221 |
| DOI: | 10.1002/psp4.12505 |
| Status: | Peer Reviewed |
| Publication Status: | Published |
| Access rights to Published version: | Open Access (Creative Commons open licence) |
| Copyright Holders: | © 2020 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics. |
| Date of first compliant deposit: | 8 March 2021 |
| Date of first compliant Open Access: | 9 March 2021 |
| RIOXX Funder/Project Grant: | Project/Grant ID RIOXX Funder Name Funder ID 1548253 [BBSRC] Biotechnology and Biological Sciences Research Council |
| URI: | https://wrap.warwick.ac.uk/149520/ |
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