Evaluation of drug‐drug interaction potential between omecamtiv mecarbil and rosuvastatin, a BCRP substrate, with a clinical study in healthy subjects and using a physiologically‐based pharmacokinetic model

Abstract Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure. In vitro, OM is an inhibitor of BCRP. Rosuvastatin, a BCRP substrate, is one of the most commonly prescribed medications in patients with heart failure. The potential for a pharmac...

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Autores principales:	Ashit Trivedi, Winnie Sohn, Priyanka Kulkarni, Pegah Jafarinasabian, Hanze Zhang, Marintan Spring, Stephen Flach, Siddique Abbasi, Jan Wahlstrom, Edward Lee, Sandeep Dutta
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270
Acceso en línea:	https://doaj.org/article/86aa2e97af2349d6999630760b8de569
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spelling	oai:doaj.org-article:86aa2e97af2349d6999630760b8de5692021-11-19T17:51:35ZEvaluation of drug‐drug interaction potential between omecamtiv mecarbil and rosuvastatin, a BCRP substrate, with a clinical study in healthy subjects and using a physiologically‐based pharmacokinetic model1752-80621752-805410.1111/cts.13118https://doaj.org/article/86aa2e97af2349d6999630760b8de5692021-11-01T00:00:00Zhttps://doi.org/10.1111/cts.13118https://doaj.org/toc/1752-8054https://doaj.org/toc/1752-8062Abstract Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure. In vitro, OM is an inhibitor of BCRP. Rosuvastatin, a BCRP substrate, is one of the most commonly prescribed medications in patients with heart failure. The potential for a pharmacokinetic (PK) drug‐drug interaction (DDI) was investigated, specifically to determine whether a single 50 mg dose of OM would impact the PKs of a single 10 mg dose of rosuvastatin in an open‐label study in 14 healthy subjects. The ratios of the geometric least‐square means (90% confidence intervals [CIs]) of rosuvastatin co‐administered with OM compared to rosuvastatin alone were 127.1% (90% CI 113.8–141.9), 132.8% (90% CI 120.7–146.1), and 154.2% (90% CI 132.8–179.1) for area under the plasma‐concentration time curve from time zero to infinity (AUCinf), area under the plasma‐concentration time curve from time zero to time of last quantifiable concentration (AUClast), and maximum observed plasma concentration (Cmax), respectively. Whereas the DDI study with rosuvastatin was conducted with the co‐administration of a single dose of OM, in the clinical setting, patients receive OM at doses of 25, 37.5, or 50 mg twice daily (b.i.d.). Hence, to extrapolate the results of the DDI study to a clinically relevant scenario of continuous b.i.d. dosing with OM, physiologically‐based pharmacokinetic (PBPK) modeling was performed to explore the potential of BCRP inhibition following continuous b.i.d. dosing of OM at the highest 50 mg dose. Modeling results indicated that following 50 mg b.i.d. dosing of OM, the predicted ratios of the geometric means (90% CIs) for rosuvastatin AUCinf and Cmax were 1.18 (90% CI 1.16–1.20) and 2.04 (90% CI 1.99–2.10), respectively. Therefore, these results suggest that OM, following multiple dose administration, is a weak inhibitor of BCRP substrates and is in accordance with that observed in the single dose OM DDI clinical study.Ashit TrivediWinnie SohnPriyanka KulkarniPegah JafarinasabianHanze ZhangMarintan SpringStephen FlachSiddique AbbasiJan WahlstromEdward LeeSandeep DuttaWileyarticleTherapeutics. PharmacologyRM1-950Public aspects of medicineRA1-1270ENClinical and Translational Science, Vol 14, Iss 6, Pp 2510-2520 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270
spellingShingle	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270 Ashit Trivedi Winnie Sohn Priyanka Kulkarni Pegah Jafarinasabian Hanze Zhang Marintan Spring Stephen Flach Siddique Abbasi Jan Wahlstrom Edward Lee Sandeep Dutta Evaluation of drug‐drug interaction potential between omecamtiv mecarbil and rosuvastatin, a BCRP substrate, with a clinical study in healthy subjects and using a physiologically‐based pharmacokinetic model
description	Abstract Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure. In vitro, OM is an inhibitor of BCRP. Rosuvastatin, a BCRP substrate, is one of the most commonly prescribed medications in patients with heart failure. The potential for a pharmacokinetic (PK) drug‐drug interaction (DDI) was investigated, specifically to determine whether a single 50 mg dose of OM would impact the PKs of a single 10 mg dose of rosuvastatin in an open‐label study in 14 healthy subjects. The ratios of the geometric least‐square means (90% confidence intervals [CIs]) of rosuvastatin co‐administered with OM compared to rosuvastatin alone were 127.1% (90% CI 113.8–141.9), 132.8% (90% CI 120.7–146.1), and 154.2% (90% CI 132.8–179.1) for area under the plasma‐concentration time curve from time zero to infinity (AUCinf), area under the plasma‐concentration time curve from time zero to time of last quantifiable concentration (AUClast), and maximum observed plasma concentration (Cmax), respectively. Whereas the DDI study with rosuvastatin was conducted with the co‐administration of a single dose of OM, in the clinical setting, patients receive OM at doses of 25, 37.5, or 50 mg twice daily (b.i.d.). Hence, to extrapolate the results of the DDI study to a clinically relevant scenario of continuous b.i.d. dosing with OM, physiologically‐based pharmacokinetic (PBPK) modeling was performed to explore the potential of BCRP inhibition following continuous b.i.d. dosing of OM at the highest 50 mg dose. Modeling results indicated that following 50 mg b.i.d. dosing of OM, the predicted ratios of the geometric means (90% CIs) for rosuvastatin AUCinf and Cmax were 1.18 (90% CI 1.16–1.20) and 2.04 (90% CI 1.99–2.10), respectively. Therefore, these results suggest that OM, following multiple dose administration, is a weak inhibitor of BCRP substrates and is in accordance with that observed in the single dose OM DDI clinical study.
format	article
author	Ashit Trivedi Winnie Sohn Priyanka Kulkarni Pegah Jafarinasabian Hanze Zhang Marintan Spring Stephen Flach Siddique Abbasi Jan Wahlstrom Edward Lee Sandeep Dutta
author_facet	Ashit Trivedi Winnie Sohn Priyanka Kulkarni Pegah Jafarinasabian Hanze Zhang Marintan Spring Stephen Flach Siddique Abbasi Jan Wahlstrom Edward Lee Sandeep Dutta
author_sort	Ashit Trivedi
title	Evaluation of drug‐drug interaction potential between omecamtiv mecarbil and rosuvastatin, a BCRP substrate, with a clinical study in healthy subjects and using a physiologically‐based pharmacokinetic model
title_short	Evaluation of drug‐drug interaction potential between omecamtiv mecarbil and rosuvastatin, a BCRP substrate, with a clinical study in healthy subjects and using a physiologically‐based pharmacokinetic model
title_full	Evaluation of drug‐drug interaction potential between omecamtiv mecarbil and rosuvastatin, a BCRP substrate, with a clinical study in healthy subjects and using a physiologically‐based pharmacokinetic model
title_fullStr	Evaluation of drug‐drug interaction potential between omecamtiv mecarbil and rosuvastatin, a BCRP substrate, with a clinical study in healthy subjects and using a physiologically‐based pharmacokinetic model
title_full_unstemmed	Evaluation of drug‐drug interaction potential between omecamtiv mecarbil and rosuvastatin, a BCRP substrate, with a clinical study in healthy subjects and using a physiologically‐based pharmacokinetic model
title_sort	evaluation of drug‐drug interaction potential between omecamtiv mecarbil and rosuvastatin, a bcrp substrate, with a clinical study in healthy subjects and using a physiologically‐based pharmacokinetic model
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/86aa2e97af2349d6999630760b8de569
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Evaluation of drug‐drug interaction potential between omecamtiv mecarbil and rosuvastatin, a BCRP substrate, with a clinical study in healthy subjects and using a physiologically‐based pharmacokinetic model

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