Heart rhythm O2 · 2026
Electrocardiographic effects of HBI-3000 (sulcardine sulfate), a new drug for termination of atrial fibrillation.
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Mason Jay W, Romano Suzanne J, Elliott Gary T, Mendzelevski Boaz, Stanworth Stephanie H, Vaglio Martino, Badilini Fabio, Gillings Mireille, Riebman Jerome B
Аннотация
BACKGROUND: HBI-3000 (sulcardine sulfate) inhibits multiple cardiac ion channels in vitro including peak sodium current, late sodium current, L-type calcium current, and the rapid component of the delayed rectifier potassium channel current.
OBJECTIVE: This study aimed to determine electrocardiographic effects, pharmacokinetics, safety, and tolerability of escalating doses of intravenously administered sulcardine in healthy volunteers.
METHODS: In this first-in-human, randomized, double-blind, placebo-controlled, serial-cohort, dose-escalation study, 47 subjects were randomized to 6 cohorts of 8, each receiving 1 of 5 single ascending 30-minute intravenous infusions (20-600 mg) of HBI-3000 (sulcardine sulfate) or placebo in a 6:2 ratio.
RESULTS: Clinically and statistically significant electrocardiographic effects were seen at the higher dose levels (180 mg, 360 mg, and 600 mg). At the probable therapeutic dose (360 mg), concentration-effect modeling predicted the following changes at the time of maximum plasma concentration (30 minutes): Fridericia-corrected QT interval, 13.50 ms; heart rate (HR), 7.70 beats per minute; PR, 17.53 ms; QRS, 7.81 ms; P-wave duration, 9.93 ms; HR corrected J to T peak interval (JTpc), -9.65 ms; and T peak to T end interval, 5.07 ms.Peak plasma concentrations fell rapidly to negligible levels at 2 hours, associated with rapid redistribution from the central compartment. No significant adverse effects were observed, and no serious adverse events were reported.
CONCLUSION: Sulcardine increased the QTc and PR intervals, QRS and P-wave durations, and HR dose dependently. The T-wave segment JTpc was significantly decreased, whereas the T peak to T end interval was significantly increased. These findings predict an anti-atrial fibrillation effect via inhibition of 1 or more cardiac ion channels. The strong block of the rapid component of the delayed rectifier potassium channel current was partially mitigated by JTp shortening, probably owing to late sodium current and L-type calcium current inhibition, reducing the risk of proarrhythmia by decreasing repolarization time.
OBJECTIVE: This study aimed to determine electrocardiographic effects, pharmacokinetics, safety, and tolerability of escalating doses of intravenously administered sulcardine in healthy volunteers.
METHODS: In this first-in-human, randomized, double-blind, placebo-controlled, serial-cohort, dose-escalation study, 47 subjects were randomized to 6 cohorts of 8, each receiving 1 of 5 single ascending 30-minute intravenous infusions (20-600 mg) of HBI-3000 (sulcardine sulfate) or placebo in a 6:2 ratio.
RESULTS: Clinically and statistically significant electrocardiographic effects were seen at the higher dose levels (180 mg, 360 mg, and 600 mg). At the probable therapeutic dose (360 mg), concentration-effect modeling predicted the following changes at the time of maximum plasma concentration (30 minutes): Fridericia-corrected QT interval, 13.50 ms; heart rate (HR), 7.70 beats per minute; PR, 17.53 ms; QRS, 7.81 ms; P-wave duration, 9.93 ms; HR corrected J to T peak interval (JTpc), -9.65 ms; and T peak to T end interval, 5.07 ms.Peak plasma concentrations fell rapidly to negligible levels at 2 hours, associated with rapid redistribution from the central compartment. No significant adverse effects were observed, and no serious adverse events were reported.
CONCLUSION: Sulcardine increased the QTc and PR intervals, QRS and P-wave durations, and HR dose dependently. The T-wave segment JTpc was significantly decreased, whereas the T peak to T end interval was significantly increased. These findings predict an anti-atrial fibrillation effect via inhibition of 1 or more cardiac ion channels. The strong block of the rapid component of the delayed rectifier potassium channel current was partially mitigated by JTp shortening, probably owing to late sodium current and L-type calcium current inhibition, reducing the risk of proarrhythmia by decreasing repolarization time.