The Effect of Carbetocin on Cardiac Repolarization: A Randomized, Placebo- and Positive-Controlled QT/QTc Study in Healthy Adults.
Carbetocin does not appear to cause clinically significant QTc prolongation in healthy adults at the studied dose.
Where it sits
this study against the rest of the carbetocin corpusSummary and findings
This study evaluated the effect of a single intravenous infusion of 650 μg of carbetocin on cardiac repolarization in healthy adults. The primary endpoint was the placebo-corrected change from baseline in QT interval (ΔΔQTc). The study found no predicted QTc prolongations of clinical or regulatory concern.
Abstract
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.
Background
This paper addresses the effect of carbetocin, an oxytocin receptor agonist, on cardiac repolarization, particularly its impact on the QT/QTc interval. Previous studies have shown that oxytocin can prolong the QT/QTc interval, but data on carbetocin specifically are limited. Understanding the cardiac safety profile of carbetocin is important, especially since it is used in clinical settings for postpartum hemorrhage prevention.
Methods
This was a randomized, placebo- and positive-controlled trial involving 42 healthy adults. Participants received a single intravenous infusion of 650 μg of carbetocin over 45 minutes. Continuous cardiodynamic ECGs were recorded from 45 minutes before to 24 hours after dosing, with the primary endpoint being the placebo-corrected change from baseline in QT interval (ΔΔQTc).
Results
The estimated mean placebo-corrected oQTcI change from baseline was 4.5 msec (90% CI: 3.4, 5.6) at a high clinical exposure level of 12.4 ng/mL. The maximum change in heart rate from baseline was 16.7 bpm. The study found no predicted QTc prolongations of clinical or regulatory concern (≥ 10 msec) at this exposure level.
Interpretation
The findings suggest that carbetocin does not significantly prolong the QT/QTc interval at the studied dose, which aligns with safety considerations for its clinical use. The effect size of 4.5 msec, while statistically significant, may not be clinically meaningful given that it is below the threshold of 10 msec typically associated with clinical concern. Limitations such as the small sample size and the focus on a single dose may affect the generalizability of the results.
Key findings
- Estimated mean placebo-corrected oQTcI change from baseline was 4.5 msec (90% CI: 3.4, 5.6).
- Mean HR change from baseline reached a maximum of 16.7 bpm.
- No predicted QTc prolongations of clinical or regulatory concern (≥ 10 msec) at the high clinical exposure level.
Limitations
- Small sample size of 42 participants.
- Single dose and short duration of observation.
- Focus on healthy adults may limit applicability to broader populations.