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Comprehensive in vitro pro-arrhythmic assays demonstrate that omecamtiv mecarbil has low pro-arrhythmic risk.

ABSTRACT: Omecamtiv mecarbil (OM) is a myosin activator (myotrope), developed as a potential therapeutic agent for heart failure with reduced ejection fraction. To characterize the potential pro-arrhythmic risk of this novel sarcomere activator, we evaluated OM in a series of International Conference on Harmonization S7B core and follow-up assays, including an in silico action potential (AP) model. OM was tested in: (i) hERG, Nav1.5 peak, and Cav1.2 channel assays; (ii) in silico computation in a human ventricular AP (hVAP) population model; (iii) AP recordings in canine cardiac Purkinje fibers (PF); and (iv) electrocardiography analysis in isolated rabbit hearts (IRHs). OM had low potency in the hERG (half-maximal inhibitory concentration [IC₅₀ ] = 125.5 µM) and Nav1.5 and Cav1.2 assays (IC₅₀ > 300 µM). These potency values were used as inputs to investigate the occurrence of repolarization abnormalities (biomarkers of pro-arrhythmia) in an hVAP model over a wide range of OM concentrations. The outcome of hVAP analysis indicated low pro-arrhythmia risk at OM concentration up to 30 µM (100-fold the effective free therapeutic plasma concentration). In the isolated canine PF assay, OM shortened AP duration (APD)₆₀ and APD₉₀ significantly from 3 to 30 µM. In perfused IRH, ventricular repolarization (corrected QT and corrected JT intervals) was decreased significantly at greater than or equal to 1 µM OM. In summary, the comprehensive proarrhythmic assessment in human and non-rodent cardiac models provided data indicative that OM did not delay ventricular repolarization at therapeutic relevant concentrations, consistent with clinical findings.

SUBMITTER: Qu Y

PROVIDER: S-EPMC8301593 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and objectiveOmecamtiv mecarbil is a novel selective cardiac myosin activator (myotrope) under investigation for the treatment of heart failure with reduced ejection fraction. The objective of this clinical study was to estimate the effect of varying degrees of renal impairment on the pharmacokinetics of omecamtiv mecarbil single dose (50 mg) under fasted conditions.MethodsThis phase I, open-label, non-randomized, parallel-group study evaluated the pharmacokinetics, safety, and tolerability of a single oral dose of omecamtiv mecarbil 50 mg in individuals with normal renal function or mild, moderate, and severe renal impairment, including end-stage renal disease requiring dialysis. Geometric least-squares mean ratios of maximum observed concentration (Cmax) and area under the plasma concentration-time curve (AUC) and 90% confidence intervals were derived for comparisons of renal impairment vs normal renal function. Participants were monitored for adverse events.ResultsThirty-one participants received treatment and completed the study. Geometric mean exposures were similar for participants with renal impairment (AUC∞ range, 2550-3220 h*ng/mL; Cmax range, 78.9-107 ng/mL) and participants with normal renal function (AUC∞, 2790 h*ng/mL; Cmax, 92.6 ng/mL), with geometric least-squares mean ratios of 85.2-125.9. Exposure was similar on dialysis vs non-dialysis days in participants with end-stage renal disease (AUC0-24, 1650 vs 1700 h*ng/mL; Cmax, 100.0 vs 107.0 ng/mL). Four participants (12.9%) reported four treatment-emergent adverse events. No deaths, treatment-emergent adverse events leading to discontinuation, or serious adverse events occurred.ConclusionsOmecamtiv mecarbil pharmacokinetics were not meaningfully affected by renal function or hemodialysis, suggesting the same dosing strategy can be used in individuals with normal renal function or renal impairment. Oral administration of omecamtiv mecarbil was not associated with major tolerability findings. This study supports omecamtiv mecarbil for the treatment of heart failure in individuals with or without renal impairment.

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Comprehensive in vitro pro-arrhythmic assays demonstrate that omecamtiv mecarbil has low pro-arrhythmic risk.

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