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Benchmarking renin suppression and blood pressure reduction of direct renin inhibitor imarikiren through quantitative systems pharmacology modeling.

Abstract：

:Multiple classes of antihypertensive drugs inhibit components of the renin-angiotensin-aldosterone system (RAAS). The primary physiological effector of the RAAS is angiotensin II (AngII) bound to the AT1 receptor (AT1-bound AngII). There is a strong non-linear feedback from AT1-bound AngII on renin secretion. Since AT1-bound AngII is not readily measured experimentally, plasma renin concentration (PRC) and/or activity (PRA) are typically measured to indicate RAAS suppression. We investigated the RAAS suppression of imarikiren hydrochloride (TAK-272; SCO-272), a direct renin inhibitor currently under clinical development. We employed a previously developed quantitative system pharmacology (QSP) model to benchmark renin suppression and blood pressure regulation with imarikiren compared to other RAAS therapies. A pharmacokinetic (PK) model of imarikiren was linked with the existing QSP model, which consists of a mechanistic representation of the RAAS pathway coupled with a model of blood pressure regulation and volume homeostasis. The PK and pharmacodynamic effects of imarikiren were calibrated by fitting drug concentration, PRA, and PRC data, and trough AT1-bound AngII suppression was simulated. We also prospectively simulated expected mean arterial pressure reduction in a cohort of hypertensive virtual patients. These predictions were benchmarked against predictions for several other (previously calibrated) RAAS monotherapies and dual-RAAS therapies. Our analysis indicates that low doses (5-10 mg) of imarikiren are comparable to current RAAS therapies, and at higher doses (25-200 mg), RAAS suppression may be equivalent to existing dual-RAAS combinations (at registered doses). This study illustrates application of QSP modeling to predict phase II endpoints from phase I data.

journal_name

J Pharmacokinet Pharmacodyn

journal_title

Journal of pharmacokinetics and pharmacodynamics

authors

Gebremichael Y,Lahu G,Vakilynejad M,Hallow KM

doi

10.1007/s10928-018-9612-y

subject

Has Abstract

pub_date

2019-02-01 00:00:00

pages

15-25

issue

eissn

1567-567X

issn

1573-8744

pii

10.1007/s10928-018-9612-y

journal_volume

pub_type

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Benchmarking renin suppression and blood pressure reduction of direct renin inhibitor imarikiren through quantitative systems pharmacology modeling.