Safety, Tolerability and Pharmacokinetics of FAAH Inhibitor V158866: A Double-Blind, Randomised, Placebo-Controlled Phase I Study in Healthy Volunteers

Background and Objective The inhibition of fatty acid amide hydrolase 1 (FAAH) has been proposed as a novel mechanism for treating pain syndromes by increasing the levels of endogenous cannabinoids (ECs). This study describes the safety, tolerability, pharmacokinetics and pharmacodynamics of V158866, a reversible FAAH inhibitor, after first administration to man. Methods 51 healthy male subjects were recruited into this double-blind, randomised, placebo-controlled, adaptive dose, phase I single (Part A) and repeated ascending dose (Part B) study. The primary outcome was the safety and tolerability of V158866. Secondary outcomes were (1) pharmacokinetics of V158866 and (2) pharmacodynamics of V158866, as assessed by changes in plasma EC concentrations. Results Single oral doses of 5-300 mg and repeated oral doses of 50-500 mg were evaluated. V158866 was well tolerated, with no apparent treatment-related effects on laboratory variables. V158866 was rapidly absorbed with a mean terminal elimination half-life of 9.6-18.3 h (Day 7; Part B). V158866 reached steady state within 2-3 days of administration, with an accumulation ratio, based on AUC(0-24h), of approximately 2 on Day 7. V158866 showed a linear relationship between dose and AUC across the entire dose range. V158866 caused reversible, dose-related increases in plasma ECs. At hemi-equilibrium, there was a sigmoidal maximum effect relationship between plasma V158866 concentrations and changes in plasma ECs. Conclusions V158866 is well tolerated, with linear pharmacokinetics suitable for once-daily administration, and reversible effects on plasma ECs. Maximum increases in plasma ECs occur with V158866 doses of 300-500 mg/day.