Search

Cenobamate is an antiseizure medication for uncontrolled focal seizures. This thorough QT study assessed the effects of therapeutic and supratherapeutic cenobamate doses (maximum recommended dose, 400 mg/day) on correct QT interval (QTc) in healthy adults (N = 108) randomly assigned to 1 of 3 treatments: (A) cenobamate (days 1‐63) up‐titrated by 50‐mg increments weekly to a 200 mg/day therapeutic dose (day 35) and then by 100 mg weekly to a 500 mg/day supratherapeutic dose (day 63), with placebo‐moxifloxacin (days −1 and 64); (B) moxifloxacin 400 mg (day −1; positive control), placebo‐cenobamate (days 1‐63), and placebo‐moxifloxacin (day 64); and (C) placebo‐moxifloxacin (day −1), placebo‐cenobamate (days 1‐64), and moxifloxacin 400 mg (day 64). The primary end point was baseline‐adjusted, placebo‐corrected QTc (ΔΔQTcF; corrected for heart rate [HR] by Fridericia's method) with cenobamate 200 and 500 mg/day. Baseline electrocardiographic parameters were balanced across groups. Mean ΔΔQTcF was negative throughout for cenobamate doses (largest: day 35, −10.8 milliseconds; day 63, −18.4 milliseconds). Based on concentration‐QTc analysis, ∆∆QTcF effect was predicted as −9.85 and −17.14 milliseconds at mean peak plasma levels of therapeutic (200 mg/day; 23.06 μg/mL) and supratherapeutic (500 mg/day; 63.96 μg/mL) doses. Cenobamate had no clinically relevant prolonging effect on electrocardiographic parameters (eg, PR, QRS); HR effects were similar to placebo. Cenobamate showed slight dose‐related shortening of QTc, but to a degree not known to be clinically relevant (no reductions ≤340 milliseconds). Cenobamate had no clinically relevant effects on HR or electrocardiographic parameters and no QTc‐prolonging effect at therapeutic/supratherapeutic doses. Cenobamate is contraindicated in patients with short‐QT syndrome and caution should be used when coadministering with drugs that shorten QT interval. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this analysis was to investigate the potential for ulixertinib (BVD-523) to prolong cardiac repolarization. The mean prolongation of the corrected QT (QTc) interval was predicted at the mean maximum drug concentrations of the recommended phase 2 dose (RP2D; 600 mg BID) and of higher concentrations. In addition, the effect of ulixertinib on other quantitative ECG parameters was assessed.Methods: In a two-part, phase 1, open-label study in adults with advanced solid tumors, 105 patients [24 in Part 1 (dose escalation) and 81 in Part 2 (cohort expansion)] were included in a QT prolongation analysis. Electrocardiograms (ECGs) extracted from 12-lead Holter monitors, along with time-matched pharmacokinetic blood samples, were collected over 12 h on cycle 1 day 1 and cycle 1 day 15 and analyzed by a core ECG laboratory.Results: A small increase in heart rate was observed on both study days (up to 5.6 bpm on day 1 and up to 7 bpm on day 15). The estimated mean changes from baseline in the study-specific QTc interval (QTcSS), at the ulixertinib Cmax, were - 0.529 ms (90% CI - 6.621, 5.562) on day 1 and - 9.202 ms (90% CI - 22.505, 4.101) on day 15. The concentration: QTc regression slopes were mildly positive but not statistically significant [0.53 (90% CI - 1.343, 2.412) and 1.16 (90% CI - 1.732, 4.042) ms per µg/mL for days 1 and 15, respectively]. Ulixertinib had no meaningful effect on PR or QRS intervals.Conclusions: Ulixertinib administered to patients with solid tumors at clinically relevant doses has a low risk for QT/QTc prolongation or any other effects on ECG parameters.Registration: The study is registered at Clinicaltrials.gov (NCT01781429) and was sponsored by BioMed Valley Discoveries. [ABSTRACT FROM AUTHOR]

Thorough QT/QTc studies have become an integral part of early drug development programs, with major clinical and regulatory implications. This analysis expands on existing pharmacodynamic models of QT interval analysis by incorporating the influence of glycemic changes on the QT interval in a semimechanistic manner. A total of 21 healthy subjects enrolled in an open-label phase 1 pilot study and provided continuous electrocardiogram monitoring and plasma glucose and insulin concentrations associated with a 24-hour baseline assessment. The data revealed a transient decrease in QTc, with peak suppression occurring approximately 3 hours after the meal. A semimechanistic modeling approach was applied to evaluate temporal delays between meals and subsequent changes that might influence QT measurements. The food effect was incorporated into a model of heart rate dynamics, and additional delayed effects of the meal on QT were incorporated using a glucose-dependent hypothetical transit compartment. The final model helps to provide a foundation for the future design and analysis of QT studies that may be confounded by meals. This study has significant implications for QT study assessment following a meal or when a cohort is receiving a medication that influences postprandial glucose concentrations. [ABSTRACT FROM AUTHOR]

Background: Macrolide antibiotics may cause QT prolongation.Objectives: To study the QT effect of a novel macrolide, solithromycin.Methods: This was a thorough QT study with a three-way crossover design performed in healthy male and female subjects to evaluate the ECG effects of a novel macrolide, solithromycin. Forty-eight subjects were randomized to receive 800 mg of intravenous (iv) solithromycin, 400 mg of oral moxifloxacin and placebo in three separate treatment periods. Continuous 12 lead ECGs were recorded at a pre-dose baseline and serially after drug administration for 24 h.Results: After the 40 min infusion of 800 mg of solithromycin, the geometric mean solithromycin peak plasma concentration (Cmax) reached 5.9 (SD: 1.30) μg/mL. Solithromycin infusion caused a heart rate increase with a peak effect of 15 bpm immediately after the end of the infusion. The change-from-baseline QTcF (ΔQTcF) was similar after dosing with solithromycin and placebo and the resulting placebo-corrected ΔQTcF (ΔΔQTcF) for solithromycin was therefore small at all timepoints with a peak effect at 4 h of only 2.8 ms (upper bound of the 90% CI: 4.9 ms). Using a linear exposure-response model, a statistically significant, slightly negative slope of -0.86 ms per ng/mL (90% CI: -1.19 to -0.53; P = 0.0001) was observed with solithromycin. The study's ability to detect small QT changes was confirmed by the moxifloxacin response. Solithromycin did not have a clinically meaningful effect on the PR or QRS interval.Conclusions: The study demonstrated that solithromycin, unlike other macrolide antibiotics, does not cause QT prolongation. [ABSTRACT FROM AUTHOR]

The article focuses on a study which examined the effects of amiodarone and quinidine on myocardial refractoriness in patients diagnosed with intraventricular conduction delay. The study included patients who are undergoing treatment for ventricular arrhythmia. It found that the administration of amiodarone increased the QT interval of the patients and reduced heart rate. Meanwhile, quinidine increased QRS interval more than amiodarone.