Abstract
Objective: Omecamtiv mecarbil is a novel small molecule that directly activates cardiac myosin and increases cardiac contractility without increasing cardiac myocyte intracellular calcium. This study evaluated the relative bioavailability, food effect, and safety of several modified-release (MR) formulations of omecamtiv mecarbil. Methods: This was a phase 1, randomized, open-label, 4-way crossover, incomplete block-design study evaluating 5 MR formulations of omecamtiv mecarbil vs. an immediate-release (IR) formulation. Materials: Healthy subjects were randomized to 1 of 30 possible sequences: within each sequence, subjects were assigned to receive a single 25-mg dose of 2 of the 6 possible formulations in the fasting and/or fed states. Results: 65 subjects were screened and enrolled; 5 were replacement subjects. Pharmacokinetic and safety data were analyzed from 62 and 63 subjects in the fasting and fed states, respectively. Compared with the IR formulation, median tmax was longer (0.5 vs. 2 – 10 hours), and mean Cmax was lower for all 5 MR formulations (262 vs. 34 – 78 ng/mL); t1/2,z was similar (18 – 21 hours). The relative bioavailability was high (> 75%) for three MR formulations but lower (< 65%) for the other two. Overall, the effect of food on omecamtiv mecarbil pharmacokinetics was minimal for four of the MR formulations. The pharmacokinetics of the inactive metabolites M3 and M4 were similar across all formulations. Conclusions: The relative bioavailability of omecamtiv mecarbil was high (> 75%) for 3 of the five MR formulations. Food had a marginal, nonclinically meaningful effect on the pharmacokinetics of the MR formulations of omecamtiv mecarbil.
Highlights
Heart failure is a clinical syndrome often coupled to impaired cardiac contractility [1]
This study evaluated the relative bioavailability, food effect, and safety of several modified-release (MR) formulations of omecamtiv mecarbil
While several pharmacological and nonpharmacological interventions have been shown to improve outcomes in patients with heart failure, global rates of morbidity and mortality remain high [3, 4]. Inotropes, such as dobutamine, dopamine, and milrinone, increase cardiac contractility by increasing cardiac myocyte intracellular calcium, but these intracellular calcium increases have been associated with important liabilities that limit their utility [5]
Summary
Heart failure is a clinical syndrome often coupled to impaired cardiac contractility [1]. While several pharmacological and nonpharmacological interventions have been shown to improve outcomes in patients with heart failure (e.g., angiotensin-converting enzyme inhibitors, beta-blockers, aldosterone antagonists, coronary revascularization, biventricular pacing [2]), global rates of morbidity and mortality remain high [3, 4]. Inotropes, such as dobutamine, dopamine, and milrinone, increase cardiac contractility by increasing cardiac myocyte intracellular calcium, but these intracellular calcium increases have been associated with important liabilities (e.g., proarrhythmia) that limit their utility [5]. A 6-hour infusion of omecamtiv mecarbil at dosing rates from 0.005 to 1.00 mg/kg/h produced linear, Period 1 (days 1 – 6)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Int. Journal of Clinical Pharmacology and Therapeutics
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
