Safety, Tolerability, and Pharmacokinetics of FAAH Inhibitor BIA 10-2474: A Double-Blind, Randomised, Placebo-Controlled Study in Healthy Volunteers.

This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of BIA 10-2474, a FAAH inhibitor, after first administration to healthy male and female subjects. Subjects (n=116) were recruited into this phase I, double-blind, randomized, placebo-controlled, single (SAD) and multiple (10-day) ascending dose (MAD) study. The primary outcome was the safety and tolerability of BIA 10-2474. Secondary outcomes were pharmacokinetics of BIA 10-2474 and pharmacodynamics, considering plasma concentrations of anandamide and three other fatty acid amides (FAAs) and leukocyte FAAH activity. Single oral doses of 0.25-100 mg and repeated oral doses of 2.5-50 mg were evaluated. BIA 10-2474 was well tolerated up to 100 mg as a single dose and up to 20 mg once daily for 10 days. In the cohort receiving repeated administrations of 50 mg, there were central nervous system adverse events in 5 of 6 subjects, one with fatal outcome, which led to early study termination. BIA 10-2474 showed a linear relationship between dose and AUC across the entire dose range and reached steady state within 5-6 days of administration, with an accumulation ratio, based on AUC0-24h , of <2 on Day 10. BIA 10-2474 was rapidly absorbed with a mean terminal elimination half-life of 8-10 h (Day 10). BIA 10-2474 caused reversible, dose-related increases in plasma FAAs. In conclusion, we propose that these data, as well as the additional data generated since the clinical trial was stopped, do not provide a complete mechanistic explanation for the tragic fatality.