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A Single Supratherapeutic Dose of Atogepant Does Not Affect Cardiac Repolarization in Healthy Adults: Results From a Randomized, Single-Dose, Phase 1 Crossover Trial.

ABSTRACT: Atogepant is a selective, oral calcitonin gene-related peptide receptor antagonist in development for preventive treatment of migraine. This randomized, double-blind, phase 1 crossover study evaluated the cardiac repolarization effect of a single supratherapeutic (300 mg) atogepant dose vs placebo in healthy adults. Moxifloxacin 400 mg was the open-label active control. The primary end point was a change from baseline in Fridericia-corrected QT intervals (ΔQTcF). Sixty participants were randomized to atogepant 300 mg, placebo, and moxifloxacin; 59 (98.3%) completed all interventions. Assay sensitivity was confirmed: lower 90% confidence interval limit for QTcF interval change from baseline (ΔΔQTcF) for moxifloxacin was >5 millisecond vs placebo at prespecified 2-, 3-, and 4-hour time points. Following single-dose atogepant 300 mg, mean atogepant ΔΔQTcF and upper 90% confidence interval limits were lower than the 10-millisecond threshold at all time points. Atogepant mean peak plasma concentration was 3197 ng/mL, area under the concentration-time curve from time 0 to time t was 16 640 ng • h/mL, area under the concentration-time curve from time 0 to 24 hours was 16 607 ng • h/mL, and median time to peak plasma concentration was 2.1 hours. The incidence of adverse events was low; no serious adverse events or elevations of liver enzymes were reported. Overall, a single supratherapeutic dose of atogepant was safe and did not impact cardiac repolarization in healthy participants.

SUBMITTER: Boinpally R

PROVIDER: S-EPMC8453716 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Single Therapeutic and Supratherapeutic Doses of Ubrogepant Do Not Affect Cardiac Repolarization in Healthy Adults: Results From a Randomized Trial.

Project description:Ubrogepant is a novel, oral calcitonin gene-related peptide receptor antagonist currently under US Food and Drug Administration (FDA) review for the acute treatment of migraine attacks. This double-blind, four-period crossover study compared the cardiac repolarization effect of therapeutic (100 mg) and supratherapeutic (400 mg) ubrogepant doses vs. placebo in healthy adults. Moxifloxacin 400 mg was used as an open-label active control, and the primary end point was change from baseline in Fridericia-corrected QT intervals (?QTcF). Assay sensitivity was demonstrated via statistically significant QTcF prolongation with moxifloxacin vs. placebo. After single oral doses of ubrogepant, the least squares mean placebo-corrected ?QTcF (??QTcF) and 90% confidence intervals (CIs) did not exceed the 10-millisecond regulatory threshold at any timepoint. The 90% CI upper bounds were 2.46 milliseconds and 2.69 milliseconds for ubrogepant 100 and 400 mg, respectively. Categorical and concentration-based analyses were consistent with the primary result, showing no significant impact of ubrogepant on cardiac repolarization.

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Peripheral blood transcriptomics_Human_Single supratherapeutic dose of acetaminophen

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2009-10-06 | GSE15158 | GEO

No effect of a single supratherapeutic dose of lersivirine, a next-generation nonnucleoside reverse transcriptase inhibitor, on corrected QT interval in healthy subjects.

Project description:The objective of this study was to investigate the effect of a supratherapeutic dose of lersivirine (LRV) on corrected QT (QTc) interval using Fridericia's equation (QTcF) in healthy subjects. In this randomized, single-dose, placebo- and active-controlled 3-way crossover study, healthy adult males (n = 48) were randomized to receive LRV (2,400 mg), moxifloxacin (400 mg), or placebo for each treatment period. Triplicate 12-lead electrocardiogram measurements were performed, PK samples were collected, and vital signs were measured. Adverse event monitoring and safety laboratory testing were performed. All subjects were white (mean age, 39 years; body mass index [BMI], 25.6 kg/m(2)) and completed the study. Following LRV administration, the upper bound of the 90% confidence interval (CI) for time-matched adjusted mean differences to placebo QTcF at each time point postdose was below the regulatory threshold of 10 ms, satisfying the criteria for a negative thorough QT/QTc study. The highest upper bound of QTcF 90% CI occurred at 6 h for LRV (3.32 ms; 90% CI, 1.47 to 5.17 ms). The study was deemed adequately sensitive as the lower bound of the 90% CI for the adjusted mean QTcF differences between moxifloxacin and placebo at the moxifloxacin historical T(max) of 3 h was >5 ms (15.29 ms; 90% CI, 13.44 to 17.14 ms). There was no statistically significant relationship between LRV exposure and placebo-adjusted change from baseline QTcF or clinically significant changes in QRS complex, pulse rate (PR) interval, heart rate, or blood pressure. LRV (2,400 mg) did not prolong the QTcF interval, and no clinically relevant electrocardiogram or vital sign changes were observed in healthy subjects.

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