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.

Trial registration: ClinicalTrials.gov NCT03700320 NCT03777059 NCT03855137 NCT03939312.

Keywords: atogepant; calcitonin gene-related peptide receptor antagonist; cardiac repolarization; migraine disorders; thorough QT study.

Conflict of interest statement

R.B., B.M., M.B., D.M., and L.B. are employees of AbbVie, and may hold AbbVie stock. L.Y. and A.P. were employees of AbbVie at the time of this study, and may hold AbbVie stock.

© 2021 Abbvie. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Placebo‐corrected least squares mean (90% confidence interval) change from predose baseline in time‐matched Fridericia‐corrected QT interval (ΔΔQTcF) following moxifloxacin administration (pharmacodynamic population; N = 59).

Figure 2

Placebo‐corrected least squares mean (90% confidence interval) change from predose baseline in time‐matched Fridericia‐corrected QT interval (ΔΔQTcF) following atogepant administration (pharmacodynamic population; N = 60).

Figure 3

Scatter plot of placebo‐corrected change from baseline intime‐matched Fridericia‐corrected QT interval (ΔΔQTcF) versus plasma atogepant concentration (pharmacodynamic population; N = 60).

Figure 4

Mean (standard deviation) plasma atogepant concentrations following 300‐mg single‐dose administration (pharmacokinetic population; N = 60) on a linear scale, and semilogarithmic scale (inset).

Figure 5

Mean (standard deviation) plasma moxifloxacin concentrations following 400‐mg single‐dose administration (pharmacokinetic population; N = 59) on a linear scale, and semilogarithmic scale (inset).