Population pharmacokinetic-pharmacodynamic modeling of omecamtiv mecarbil, a cardiac myosin activator, in healthy volunteers and patients with stable heart failure

2015 ◽  
Vol 55 (11) ◽  
pp. 1236-1247 ◽  
Author(s):  
Thuy Vu ◽  
Peiming Ma ◽  
Jim J. Xiao ◽  
Yow-Ming C. Wang ◽  
Fady I. Malik ◽  
...  
Keyword(s):  
Heart Failure ◽  
Healthy Volunteers ◽  
Pharmacodynamic Modeling ◽  
Population Pharmacokinetic ◽  
Cardiac Myosin ◽  
Omecamtiv Mecarbil

scholarly journals Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure

2020 ◽  
Author(s):  
John R. Teerlink ◽  
Rafael Diaz ◽  
G. Michael Felker ◽  
John J.V. McMurray ◽  
Marco Metra ◽  
...  
Keyword(s):  
Heart Failure ◽  
Systolic Heart Failure ◽  
Cardiac Myosin ◽  
Omecamtiv Mecarbil

scholarly journals Population Pharmacokinetic-Pharmacodynamic Modeling of Captopril in Healthy Volunteers

2001 ◽  
Vol 9 (1) ◽  
pp. 37
Author(s):  
So-Young Yi ◽  
Kyun-Seop Bae ◽  
Hyeong-Seok Lim ◽  
Joo-Youn Cho ◽  
Kyung-Sang Yu ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Pharmacodynamic Modeling ◽  
Population Pharmacokinetic

P5440Systolic/diastolic effects of chronic treatment with omecamtiv mecarbil in minipigs with post-myocardial infarction Heart Failure with reduced Ejection Fraction (HFrEF)

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
D Caillaud ◽  
X Baudot ◽  
L Gouraud ◽  
L Lucats ◽  
M P Pruniaux ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Ejection Fraction ◽  
Healthy Volunteers ◽  
Chronic Treatment ◽  
Positive Inotropic Effect ◽  
Post Myocardial Infarction ◽  
Inotropic Effect ◽  
Reduced Ejection Fraction ◽  
Omecamtiv Mecarbil

Abstract Background Omecamtiv mecarbil (OM), a novel myosin ATPase activator, is currently developed for the treatment of Heart Failure with reduced Ejection Fraction (HFrEF). Phase I in healthy volunteers and patients showed that the positive inotropic effect of OM was associated with an impairment of diastolic function as assessed by change in E peak, e' wave and E/e' ratio. Purpose The diastolic impact of chronic treatment with OM has not been described yet. This study investigates the balance between positive inotropic effect and the diastolic impairment after chronic treatment with OM in a post-myocardial infarction (Post-MI) swine model of HFrEF. Methods HFrEF was induced in minipigs after myocardial infarction caused by a 150-min left anterior descending (LAD) artery occlusion performed under angiography. HFrEF minipigs were treated with OM at 3 mg/kg PO BID for 15 days (n=4), a dose known to increase systolic ejection time (SET) by ∼50 ms as achieved in healthy volunteers and patients at plasma levels between 200–300 ng/ml. Echocardiogram was performed before and after 15 days of treatment with OM. An additional echocardiogram was conducted 7 days after the last administration. Results One year after MI, minipigs displayed increased left ventricular end-diastolic volume index (LVEDVi 151±3.7ml/m2 vs 100±8.9ml/m2 before infarction) and decreased LVEF (42±2.5% vs 68±4.4% before infarction) associated with a pseudo-normal mitral pattern. A two-week treatment with OM increased SET by 64ms (p<0.0001 vs before treatment) and EF to 49±3.8% (p=0.07 vs before treatment) as well as it improved SVi by 13%. This inotropic effect was associated with a decrease of mitral E peak (p=0.01 vs before treatment) and e' waves, and with the prolongation of deceleration time (p<0.05 vs before treatment). OM treatment was associated with marked reduction of LVEDVi to 117±13.2ml/m2 (p<0.05 vs before treatment) concomitant with a ∼20% increase in diastolic septum and posterior wall thicknesses. None of these systolic or diastolic effects remained 7 days post OM treatment completion. Conclusion Similarly to clinical description, OM treatment increased LVEF and SVi principally through extension of SET. It provides positive inotropic effects associated with diastolic impairment resulting in impaired ventricular filling as assessed by LVEDVi decrease and the thickening of ventricular wall in diastole. Whether this profile will allow a beneficial reverse remodeling, needs to be investigated in a longer chronic study. Acknowledgement/Funding Sanofi sponsored study

scholarly journals Human hypertrophic cardiomyopathy mutation R712L suppresses the working stroke of cardiac myosin and can be rescued by omecamtiv mecarbil

2020 ◽  
Author(s):  
Aaron Snoberger ◽  
Bipasha Barua ◽  
Jennifer L. Atherton ◽  
Henry Shuman ◽  
Eva Forgacs ◽  
...  
Keyword(s):  
Heart Failure ◽  
Hypertrophic Cardiomyopathy ◽  
Atpase Activity ◽  
Single Molecule ◽  
Cardiac Failure ◽  
Flow Chamber ◽  
Severe Form ◽  
Gliding Motility ◽  
Cardiac Myosin ◽  
Omecamtiv Mecarbil

AbstractHypertrophic cardiomyopathies (HCMs) are the leading cause of acute cardiac failure in young individuals. Over 300 mutations throughout β-cardiac myosin, including in the motor domain, are associated with HCM. A β-cardiac myosin motor mutation (R712L) leads to a severe form of HCM. Actin-gliding motility of R712L-myosin is inhibited, despite near normal ATPase kinetics. By optical trapping, the working stroke of R712L-myosin was decreased 4-fold, but actin-attachment durations were normal. A prevalent hypothesis that HCM mutants are hypercontractile is thus not universal. R712 is adjacent to the binding site of the heart failure drug omecamtiv mecarbil (OM). OM suppresses the working stroke of normal β-cardiac myosin, but remarkably, OM rescues the R712L-myosin working stroke. Using a flow chamber to interrogate a single molecule during buffer exchange, we found OM rescue to be reversible. Thus, the R712L mutation uncouples lever arm rotation from ATPase activity and this inhibition is rescued by OM.

scholarly journals Heart failure drug changes the mechanoenzymology of the cardiac myosin powerstroke

2017 ◽  
Vol 114 (10) ◽  
pp. E1796-E1804 ◽  
Author(s):  
John A. Rohde ◽  
David D. Thomas ◽  
Joseph M. Muretta
Keyword(s):  
Heart Failure ◽  
Atp Hydrolysis ◽  
Cardiac Contractility ◽  
Cardiac Myosin ◽  
Transient Time ◽  
Time Resolved ◽  
Phosphate Release ◽  
Omecamtiv Mecarbil ◽  
Biochemical State ◽  
Kinetics Of

Omecamtiv mecarbil (OM), a putative heart failure therapeutic, increases cardiac contractility. We hypothesize that it does this by changing the structural kinetics of the myosin powerstroke. We tested this directly by performing transient time-resolved FRET on a ventricular cardiac myosin biosensor. Our results demonstrate that OM stabilizes myosin’s prepowerstroke structural state, supporting previous measurements showing that the drug shifts the equilibrium constant for myosin-catalyzed ATP hydrolysis toward the posthydrolysis biochemical state. OM slowed the actin-induced powerstroke, despite a twofold increase in the rate constant for actin-activated phosphate release, the biochemical step in myosin’s ATPase cycle associated with force generation and the conversion of chemical energy into mechanical work. We conclude that OM alters the energetics of cardiac myosin’s mechanical cycle, causing the powerstroke to occur after myosin weakly binds to actin and releases phosphate. We discuss the physiological implications for these changes.

Omecamtiv mecarbil: a new cardiac myosin activator for the treatment of heart failure

2015 ◽  
Vol 25 (1) ◽  
pp. 117-127 ◽  
Author(s):  
Licette CY Liu ◽  
Bernard Dorhout ◽  
Peter van der Meer ◽  
John R Teerlink ◽  
Adriaan A Voors
Keyword(s):  
Heart Failure ◽  
Cardiac Myosin ◽  
Omecamtiv Mecarbil
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