Cerebrospinal Fluid and Plasma Concentrations of Atogepant in Humans

The aim of this study was to determine the cerebrospinal fluid (CSF) to plasma concentration ratio of atogepant. Healthy adult participants (N = 28) were enrolled into this phase 1, open-label study and received atogepant 60 mg once daily for 8 days. Steady-state atogepant concentrations were determined from CSF samples collected on Day 6 at 2 (n = 12) or 6 (n = 12) h postdose, and plasma samples were collected over 24 h after the Day 7 dose. Descriptive statistics for the atogepant CSF-to-plasma (CSF/plasma) ratio were calculated for each time point. The safety and tolerability profiles of atogepant were evaluated by clinical assessment of adverse events, physical examinations, 12-lead ECGs, laboratory tests, and vital sign measurements. The majority of adverse events were nonserious and mild in severity. Two participants discontinued the study. One due to asymptomatic moderately elevated liver enzymes and another due to mild confusional state/insomnia. Steady-state mean ± SD plasma_total (bound + unbound) and CSF atogepant concentrations at 2 h were 652.54 ± 385.40 and 0.49 ± 0.78 ng/mL, and at 6 h were 163.14 ± 85.87 and 1.21 ± 1.14 ng/mL, respectively. The mean atogepant CSF/plasma_total concentration ratio was 0.1% at 2 h and 0.7% at 6 h postdose. CSF/plasma_unbound concentration ratios at 2 and 6 h were 1.4% and 14.3%, respectively. Although the CNS penetration was low, considering atogepant's high affinity to CGRP receptors (Ki = 0.016 ng/mL) and a CIDV (capsaicin-induced dermal vasodilation) EC₅₀ (half maximal effective concentration) value of 0.91 ng/mL, more research is needed to determine if atogepant acts both centrally and peripherally to prevent/treat a migraine attack.