Acute Hemodynamic Effects and Tolerability of Phosphodiesterase-1 Inhibition With ITI-214 in Human Systolic Heart Failure.

Abstract

BACKGROUND:

PDE1 (phosphodiesterase type 1) hydrolyzes cyclic adenosine and guanosine monophosphate. ITI-214 is a highly selective PDE1 inhibitor that induces arterial vasodilation and positive inotropy in larger mammals. Here, we assessed pharmacokinetics, hemodynamics, and tolerability of single-dose ITI-214 in humans with stable heart failure with reduced ejection fraction.

METHODS:

Patients with heart failure with reduced ejection fraction were randomized 3:1 to 10, 30, or 90 mg ITI-214 single oral dose or placebo (n=9/group). Vital signs and electrocardiography were monitored predose to 5 hours postdose and transthoracic echoDoppler cardiography predose and 2-hours postdose.

RESULTS:

Patient age averaged 54 years; 42% female, and 60% Black. Mean systolic blood pressure decreased 3 to 8 mm Hg (P<0.001) and heart rate increased 5 to 9 bpm (P≤0.001 for 10, 30 mg doses, RM-ANCOVA). After 4 hours, neither blood pressure or heart rate significantly differed among cohorts (supine or standing). ITI-214 increased mean left ventricular power index, a relatively load-insensitive inotropic index, by 0.143 Watts/mL2·104 (P=0.03, a +41% rise; 5-71 CI) and cardiac output by 0.83 L/min (P=0.002, +31%, 13-49 CI) both at the 30 mg dose. Systemic vascular resistance declined with 30 mg (-564 dynes·s/cm-5, P<0.001) and 90 mg (-370, P=0.016). Diastolic changes were minimal, and no parameters were significantly altered with placebo. ITI-214 was well-tolerated. Five patients had mild-moderate hypotension or orthostatic hypotension recorded adverse events. There were no significant changes in arrhythmia outcome and no serious adverse events.

CONCLUSIONS:

Single-dose ITI-214 is well-tolerated and confers inodilator effects in humans with heart failure with reduced ejection fraction. Further investigations of its therapeutic utility are warranted. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03387215.

• Authors: Nisha A Gilotra, Adam D DeVore, Thomas J Povsic, Allison G Hays, Virginia S Hahn, Tolu A Agunbiade, Allison DeLong, Andrew Satlin, Richard Chen, Robert Davis, David A Kass
• Journal: Circulation. Heart failure (Circ Heart Fail) Vol. 14 Issue 9 Pg. e008236 (09 2021) ISSN: 1941-3297 [Electronic] United States
• PMID: 34461742 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Heterocyclic Compounds, 4 or More Rings
• ITI-214
• Phosphoric Diester Hydrolases

Topics

• Aged
• Female
• Heart Failure, Systolic (drug therapy, physiopathology)
• Heart Rate (drug effects)
• Heart Ventricles (physiopathology)
• Hemodynamics (drug effects)
• Heterocyclic Compounds, 4 or More Rings (pharmacology)
• Humans
• Male
• Middle Aged
• Phosphoric Diester Hydrolases (drug effects, metabolism)
• Stroke Volume (drug effects)
• Vascular Resistance (drug effects, physiology)
• Ventricular Dysfunction, Left
• Ventricular Function, Left (drug effects)