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

Abstract

Background and ObjectiveThe 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.Methods51 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.ResultsSingle 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.ConclusionsV158866 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s40268-016-0127-y) contains supplementary material, which is available to authorized users.

Breaking barriers to novel analgesic drug development

“…An irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, failed to reduce pain from osteoarthritis of the knee, in spite of decreasing FAAH activity by >96% and substantially increasing fatty acid amide endogenous substrates, and many preclinical studies showing efficacy in models of inflammatory pain 254 . In spite of this FAAH failure, others are entering clinical trials 255,256 and there is preliminary human genetic support for FAAH involvement in cold pain sensitivity 257 . Was the failure of the Pfizer compound a failure to access FAAH in the CNS?…”

Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors

“…Although MAGL inhibitors (such as 151, a moderately selective inhibitor) rather than FAAH inhibitors were previously reported to induce CB1-dependent side effects (hypomotility and hypothermia), 178 headache, dizziness, somnolence and fatigue) were mainly observed at the highest doses (500 mg daily). 180 Overall, V158866 was tolerated and did not trigger severe adverse effects even post a high dose (500 mg daily). Accordingly, FAAH can be still regarded as a safe target for therapeutic intervention.…”

The cannabinoid system and pain

“…The wealth of preclinical data demonstrating efficacy of FAAH inhibition as an analgesic strategy has led to completion of Phase I trials in humans (PF-04457845 - Li et al, 2012; V158866 - Pawsey et al, 2016). However, despite being well-tolerated and producing significant elevations in peripheral blood levels of AEA, PF-04457845 failed to produce significant analgesia in a Phase II trial in late-stage osteoarthritis (OA) patients (Huggins et al, 2012).…”