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A5690 - Electrocardiographic Effects of Esuberaprost (BPS‑314d) Compared to Placebo and Moxifloxacin (a Positive Control) in Healthy Adult Subjects: A Thorough QT Study
Author Block: K. R. von Kessler1, K. Whitehurst2, B. Darpo3, S. Hossack4, X. Chen5, M. Dunn5, E. A. Duvall1, J. Shin1, P. Sista1; 1Lung Biotechnology, Silver Spring, MD, United States, 2Covance, Evansville, IN, United States, 3iCardiac, Rochester, NY, United States, 4Covance, Leeds, United Kingdom, 5Covance, Madison, WI, United States.
Introduction
The prostacyclin analogue beraprost, a mixture of 4 stereoisomers, is available for treatment of PAH in Asia. The pharmacologically active isomer esuberaprost is undergoing clinical evaluation in a Phase 3 study as a modified release tablet. The objective of this study was to assess the effect of therapeutic and supratherapeutic exposure levels of esuberaprost, achieved via 15 and 30 µg oral solution doses, respectively, on cardiac repolarization (QT interval corrected for heart rate using Fridericia’s formula [QTcF]) in healthy adult subjects.
Methods
This was a double-blind, randomized, single-dose, 4-period, placebo- and active-controlled, crossover study of esuberaprost as an oral solution. Healthy adult subjects were randomly assigned to receive 15 or 30 µg esuberaprost, placebo, or moxifloxacin. Sixty subjects were enrolled to have at least 45 subjects completing the study. During protocol-specified extraction windows, 12-lead electrocardiogram tracings were extracted from continuous Holter recordings.
Results
Sixty subjects (47 males and 13 females) were enrolled and 58 subjects completing the study were included in the pharmacokinetic/QTC population.
Mean esuberaprost plasma concentration profiles were characterized by rapid absorption and tmax values were similar for both treatments. Following Cmax, mean plasma concentrations generally declined in a monophasic manner with similar mean t1/2.
Esuberaprost caused a transient heart rate increase with the largest mean placebo-corrected changefrom-baseline (αα) heart rate of 10.8 and 15.9 bpm seen 10 minutes after dosing with 15 and 30 μg, respectively. The effect on the QTcF was small with mean ∆∆QTcF of 7.1 msec (90% CI: 5.1 to 9.0) and 11.3 msec (90% CI: 9.4 to 13.3), respectively, at 20 minutes post dose. There was a very shallow, but significant, relationship between esuberaprost plasma concentration and QTcF, with a slope of 0.040 msec/pg/mL. Predicted ∆∆QTcF was 5.89 msec (90% CI: 4.66 to 7.11) and 9.58 msec (90% CI: 7.80 to 11.36) at the observed geometric mean Cmax for both treatments, 149 and 241 pg/mL, respectively.
Esuberaprost was well tolerated with the majority of reported treatment emergent adverse events being mild in severity and typical of prostacyclins e.g. headache, flushing, and nausea. No serious adverse events were reported.
Conclusions
Results demonstrated that at therapeutic and supratherapeutic exposures, the effect of esuberaprost on QTcF was small with mean ∆∆QTcF of 7.1 and 11.3 msec, respectively, at 20 minutes post-dose (approximate tmax). Although slightly above the pre-specified 10 msec threshold for QTcF, clinical concern for this mild effect at supratherapeutic exposures is likely minimal.