Atogepant Is Not Associated With Clinically Meaningful Alanine Aminotransferase Elevations in Healthy Adults

Clin Transl Sci. 2021 Mar;14(2):599-605. doi: 10.1111/cts.12917. Epub 2020 Nov 24.


Atogepant is a potent, selective, oral calcitonin gene-related peptide (CGRP) receptor antagonist in development for migraine prevention. The chemical structure of atogepant is distinct from previous CGRP receptor antagonists, which were associated with elevated serum alanine aminotransferase (ALT) in clinical trials. Here, we report the safety, tolerability, and pharmacokinetics (PKs) of a once-daily supratherapeutic dose (170 mg) of atogepant for 28 days from a randomized, double-blind, placebo-controlled phase I trial in healthy participants. Overall safety, hepatic safety, and plasma PK parameters were evaluated. Thirty-four participants aged 23-55 years enrolled; 28 (82.4%) completed the study in accordance with the protocol. Multiple doses of 170 mg atogepant for 28 consecutive days were generally well-tolerated. All adverse events (AEs; reported in 87.0% of the atogepant group; 72.7%, placebo) were mild in severity except one serious AE of subarachnoid hemorrhage due to a bicycle accident and not considered related to treatment. There were two discontinuations due to AEs, both with atogepant, one considered possibly related to treatment. Over 28 days of treatment, no participant receiving atogepant had an ALT elevation above 1.5 × upper limit of normal. Change from baseline in serum ALT levels was not different between atogepant and placebo. Atogepant is rapidly absorbed (median time to maximum plasma concentration, ~ 2 hours) with an apparent terminal half-life of ~ 11 hours, and no evidence of accumulation after once-daily dosing. Overall, atogepant at a high oral dose is safe and well-tolerated in healthy participants with no clinically meaningful elevations in ALT.

Trial registration: NCT03700320 NCT03777059 NCT03855137 NCT03939312.

Publication types

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

MeSH terms

  • Administration, Oral
  • Adult
  • Alanine Transaminase / blood*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Healthy Volunteers
  • Humans
  • Liver / drug effects*
  • Liver / enzymology
  • Liver Function Tests
  • Male
  • Middle Aged
  • Migraine Disorders / prevention & control
  • Piperidines / administration & dosage
  • Piperidines / adverse effects*
  • Piperidines / pharmacokinetics
  • Placebos / administration & dosage
  • Placebos / adverse effects
  • 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


  • Piperidines
  • Placebos
  • Pyridines
  • Pyrroles
  • Spiro Compounds
  • atogepant
  • Alanine Transaminase

Associated data