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

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 E-max model was 137 milliseconds. LVOTSV increased linearly from baseline by 1.6mL per 100ng/mL of omecamtiv mecarbil. Model-based simulations for several immediate-release oral dose regimens (37.5, 50, and 62.5mg 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.