Pharmacokinetic and pharmacodynamic assessments of atogepant in healthy male adults: Results from phase 1 studies

Atogepant, an oral calcitonin gene-related peptide receptor antagonist, is approved for the preventive treatment of migraine in adults. This manuscript characterizes the safety, tolerability, pharmacokinetics and pharmacokinetic/pharmacodynamic relationship of atogepant in healthy males. Data from two single-ascending dose phase 1 studies of atogepant were utilized to characterize pharmacokinetics and demonstrate proof of activity of atogepant in a capsaicin-induced dermal vasodilatation model and to determine the dosage(s) that results in 90% inhibition of capsaicin-induced dermal vasodilatation (effective concentration, EC90) over 24 hours. Single (0.4−200 mg) doses of atogepant were generally well tolerated by healthy participants with no treatment-related study discontinuations. Atogepant was rapidly absorbed with peak plasma concentrations occurring 1–2 hours post dose and a mean elimination half-life of ∼11 hours. Based on the capsaicin-induced dermal vasodilatation and pharmacokinetic/pharmacodynamic models, atogepant has an estimated EC90 of 13.6 nM which was reached within 30 minutes at therapeutic doses and maintained for 24 hours at dosages of 60 mg once daily and 30 and 60 mg twice daily. Atogepant reached effective concentrations within 0.5 hours which were maintained for 24 hours at dosages of 60 mg once daily and 30 and 60 mg twice daily for the prevention of migraine. Clinical Trial EudraCT Numbers: 2011-005020-18 (Study 1) and 2012-001192-36 (Study 2).