title: Safety, Tolerability and Pharmacokinetics of FAAH Inhibitor V158866: A Double-Blind, Randomised, Placebo-Controlled Phase I Study in Healthy Volunteers.
abstract: 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 AUC0-24h, 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.
authors.affiliation: Vernalis (R&D) Ltd., 100 Berkshire Place, Wharfedale Road, Winnersh, Berkshire, RG41 5RD, UK.|Circassia, Oxford, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Pawsey
authors.affiliation: Vernalis (R&D) Ltd., 100 Berkshire Place, Wharfedale Road, Winnersh, Berkshire, RG41 5RD, UK. m.wood@vernalis.com.
authors.forename: Mike
authors.initials: M
authors.lastname: Wood
authors.affiliation: Vernalis (R&D) Ltd., 100 Berkshire Place, Wharfedale Road, Winnersh, Berkshire, RG41 5RD, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Browne
authors.affiliation: Jade Consultants (Cambridge) Ltd., Cambridge, UK.
authors.forename: Kirsteen
authors.initials: K
authors.lastname: Donaldson
authors.affiliation: Akranim Ltd., Maidstone, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Christie
authors.affiliation: Hammersmith Medicines Research, London, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Warrington
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000581:Amidohydrolases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000097:blood / Q000652:urine; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D053719:Tandem Mass Spectrometry; D016896:Treatment Outcome; D055815:Young Adult; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D000099252:Fatty Acid Amide Hydrolases