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

Clin Pharmacol Drug Dev. 2021 Sep;10(9):1099-1107. doi: 10.1002/cpdd.940. Epub 2021 May 4.

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.

Publication types

  • Clinical Trial, Phase I
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Area Under Curve
  • Calcitonin Gene-Related Peptide Receptor Antagonists / administration & dosage
  • Calcitonin Gene-Related Peptide Receptor Antagonists / adverse effects*
  • Calcitonin Gene-Related Peptide Receptor Antagonists / pharmacokinetics
  • Cross-Over Studies
  • Double-Blind Method
  • Electrocardiography
  • Female
  • Humans
  • Long QT Syndrome / chemically induced*
  • Male
  • Moxifloxacin / adverse effects*
  • Piperidines / administration & dosage
  • Piperidines / adverse effects*
  • Piperidines / pharmacokinetics
  • Pyridines / administration & dosage
  • Pyridines / adverse effects*
  • Pyridines / pharmacokinetics
  • Pyrroles / administration & dosage
  • Pyrroles / adverse effects*
  • Pyrroles / pharmacokinetics
  • Spiro Compounds / administration & dosage
  • Spiro Compounds / adverse effects*
  • Spiro Compounds / pharmacokinetics
  • Young Adult

Substances

  • Calcitonin Gene-Related Peptide Receptor Antagonists
  • Piperidines
  • Pyridines
  • Pyrroles
  • Spiro Compounds
  • atogepant
  • Moxifloxacin

Associated data

  • ClinicalTrials.gov/NCT03700320
  • ClinicalTrials.gov/NCT03777059
  • ClinicalTrials.gov/NCT03855137
  • ClinicalTrials.gov/NCT03939312