Abstract / Summary
Carbetocin is an oxytocin receptor agonist used for postpartum hemorrhage prevention. While oxytocin is known to transiently prolong the QT/QTc interval, robust QTc data for carbetocin are limited. Carbetocin is known to elevate HR, which can impact QTc analyses; thus, a dose that did not overly elevate HR was important to select. This randomized, placebo- and positive-controlled trial evaluated the effect of a single intravenous infusion of a supratherapeutic dose (650 μg) of carbetocin over 45 min on cardiac repolarization in healthy adults (N = 42). Continuous cardiodynamic ECGs were recorded from 45 min before through 24 h after dosing. The primary endpoint was placebo-corrected change from baseline in QT interval (ΔΔQTc) using the most appropriate heart rate (HR) correction method. The primary analysis was based on exposure-response modeling of the relationship between carbetocin plasma concentrations and ΔΔQTc, to identify an effect ≥ 10 msec at the high clinical exposure. During intravenous infusion of carbetocin, the mean HR change from baseline reached a maximum of 16.7 bpm. Multiple correction methods for HR were assessed, and the placebo-corrected, optimized, individualized heart rate-corrected QT interval (oQTcI) was found to be adequate. The estimated mean placebo-corrected oQTcI change from baseline was 4.5 msec (90% CI: 3.4, 5.6) at the high clinical exposure level of 12.4 ng/mL following a single intravenous infusion of 867 μg/h carbetocin. Exposure-response models for carbetocin established no predicted QTc prolongations of clinical or regulatory concern (≥ 10 msec) at the high clinical exposure level. Trial Registration: ClinicalTrials.gov Registration: NCT05924321.