title: Population pharmacokinetic-pharmacodynamic modeling of omecamtiv mecarbil, a cardiac myosin activator, in healthy volunteers and patients with stable heart failure.
abstract: Data from 3 clinical trials of omecamtiv mecarbil in healthy volunteers and patients with stable heart failure (HF) were analyzed using a nonlinear mixed-effects model to investigate omecamtiv mecarbil's pharmacokinetics and relationship between plasma concentration and systolic ejection time (SET) and Doppler-derived left ventricular outflow tract stroke volume (LVOTSV). Omecamtiv mecarbil pharmacokinetics were described by a linear 2-compartment model with a zero-order input rate for intravenous administration and first-order absorption for oral administration. Oral absorption half-life was 0.62 hours, and absolute bioavailability was estimated as 90%; elimination half-life was approximately 18.5 hours. Variability in pharmacokinetic parameters was not explained by patient baseline characteristics. Omecamtiv mecarbil plasma concentration was directly correlated with increases in SET and LVOTSV between healthy volunteers and patients with HF. The maximum increase from baseline in SET (delta SET) estimated by an Emax model was 137 milliseconds. LVOTSV increased linearly from baseline by 1.6 mL per 100 ng/mL of omecamtiv mecarbil. Model-based simulations for several immediate-release oral dose regimens (37.5, 50, and 62.5 mg dosed every 8, 12, and 24 hours) showed that a pharmacodynamic effect (delta SET ≥20 milliseconds) could be maintained in the absence of excessive omecamtiv mecarbil plasma concentrations.
authors.affiliation: Clinical Pharmacology, M&S, Medical Sciences, Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Thuy
authors.initials: T
authors.lastname: Vu
authors.affiliation: Clinical Pharmacology, M&S, Medical Sciences, Amgen Inc., Thousand Oaks, CA, USA.|Current address: GlaxoSmith Kline, Shanghai, China.
authors.forename: Peiming
authors.initials: P
authors.lastname: Ma
authors.affiliation: Clinical Pharmacology, M&S, Medical Sciences, Amgen Inc., Thousand Oaks, CA, USA.|Current address: Clovis Oncology, San Francisco, CA, USA.
authors.forename: Jim J
authors.initials: JJ
authors.lastname: Xiao
authors.affiliation: Clinical Pharmacology, M&S, Medical Sciences, Amgen Inc., Thousand Oaks, CA, USA.|Current address: Office of Clinical Pharmacology, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Yow-Ming C
authors.initials: YM
authors.lastname: Wang
authors.affiliation: Cytokinetics Inc., South San Francisco, CA, USA.
authors.forename: Fady I
authors.initials: FI
authors.lastname: Malik
authors.affiliation: Clinical Pharmacology, M&S, Medical Sciences, Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chow
mesh_terms: D000328:Adult; D000368:Aged; D024722:Cardiac Myosins / Q000378:metabolism; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D064368:Healthy Volunteers; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D013318:Stroke Volume / Q000187:drug effects; D013599:Systole / Q000187:drug effects; D014508:Urea / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: C547293:omecamtiv mecarbil; D014508:Urea; D024722:Cardiac Myosins
keywords: CK-1827452; NONMEM; cardiac myosin activator; inotrope; omecamtiv mecarbil; population PK-PD; stable heart failure; systolic ejection time