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.

Keywords: adenosine; blood pressure; cardiac output; heart failure; inotrope; vasodilation.

Figures

Figure 1.. Pharmacokinetics of phosphodiesterase-1 inhibitor ITI-214 in patients with heart failure with reduced ejection fraction.

Time course of plasma ITI-214 concentrations in each dosing cohort shows dose dependent levels. Peak concentration was achieved within 45 minutes after oral dosing, remaining at this level out to 2 hours post dose. Data are displayed as mean ± 95% CI. Results of 2W repeated measures ANOVA : p−9 for dose, time, and dose*time interaction. Tukey multiple comparisons test shown: 10 vs 30 mg: * p≤0.007, # p=0.15, † p<0.001; 10 vs 90 mg: $ p=0.01, ‡ p<0.001; 30 vs 90 mg: § p<0.001.

Figure 2.. Blood pressure and heart rate changes from baseline through 2-hour post-dosing monitoring period as well as at 4-hours post-dosing with ITI-214 or placebo in patients with heart failure with reduced ejection fraction.

Data are mean ± 95% CI. P-values for within dose-group regressions over 2-hour period are displayed in each plot. See main text for covariance results versus placebo at each ITI-214 dose.

Figure 3.. Hemodynamic responses comparing baseline to 2-hours post-dosing with single dose of phosphodiesterase-1 inhibitor - ITI-214, or placebo.

A) Panels display violin plots for absolute change in each parameter before and after dosing, with all raw data, and median, 25th, and 75th percentile range. Groups received placebo (P), or 10, 30, 90 mg ITI-214. P values above each group are from analysis of covariance with placebo comparison and baseline values for each patient serving as covariates, and the dependent variable being change between pre-post measurements. B) Percent change for mean LV power index (mPWRi) and cardiac output for pre versus post dose in each patient. P-values show results for Wilcoxon test of pre-post percent change for each patient within a dose cohort, without a multiple comparisons correction. Ea: effective arterial elastance; EDV: end diastolic volume; EF: ejection fraction; E/E’: ratio of early transmitral flow/tissue velocity; IVRT: isovolumic relaxation time; mPWRi: mean LV power index; SVR: systemic vascular resistance.