Assessment of the pharmacology and tolerability of PF‐04457845, an irreversible inhibitor of fatty acid amide hydrolase‐1, in healthy subjects

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Inhibition of fatty acid amide hydrolase‐1 (FAAH1) and the subsequent elevation of fatty acid amides has been proposed as a strategy to induce the analgesic properties of cannabinoids without the accompanying negative side effects such as impairment in cognition, motor control and predisposition to psychoses. PF‐04457845 is a potent and selective irreversible FAAH1 inhibitor which has been shown to elevate fatty acid amide concentrations in animal models and induce responses in behavioural models suggestive of analgesia. WHAT THIS STUDY ADDS • This study is the first to investigate a FAAH1 inhibitor in humans. PF‐04457845 is well tolerated following single and multiple dosing to healthy volunteers and has pharmacokinetic and pharmacodynamic properties that make nearly complete inhibition of FAAH1 possible with once daily dosing. AIMS To evaluate the pharmacology and tolerability of PF‐04457845, an orally available fatty acid amide hydrolase‐1 (FAAH1) inhibitor, in healthy subjects. METHODS Double‐blind, randomized, placebo‐controlled single and multiple rising dose studies and an open‐label, randomized, food effect study were conducted. Plasma and urine PF‐04457845 concentrations, plasma fatty acid amide concentrations and FAAH1 activity in human leucocytes were measured. Tolerability, including effects on cognitive function, were assessed. RESULTS PF‐04457845 was rapidly absorbed (median tmax 0.5–1.2 h). Exposure increased supraproportionally to dose from 0.1 to 10 mg and proportionally between 10 and 40 mg single doses. The pharmacokinetics appeared dose proportional following 14 days once daily dosing between 0.5 and 8 mg. Steady‐state was achieved by day 7. Less than 0.1% of the dose was excreted in urine. Food had no effect on PF‐04457845 pharmacokinetics. FAAH1 activity was almost completely inhibited (>97%) following doses of at least 0.3 mg (single dose) and 0.5 mg once daily (multiple dose) PF‐04457845. Mean fatty acid amide concentrations increased (3.5‐ to 10‐fold) to a plateau and then were maintained following PF‐04457845. FAAH1 activity and fatty acid amide concentrations returned to baseline within 2 weeks following cessation of dosing at doses up to 4 mg. There was no evidence of effects of PF‐04457845 on cognitive function. PF‐04457845, at doses up to 40 mg single dose and 8 mg once daily for 14 days, was well tolerated. CONCLUSIONS PF‐04457845 was well tolerated at doses exceeding those required for maximal inhibition of FAAH1 activity and elevation of fatty acid amides.

Fatty Acid Amide Hydrolase Inhibition by JNJ‐42165279: A Multiple‐Ascending Dose and a Positron Emission Tomography Study in Healthy Volunteers

“…A recent study using a 4 mg once‐daily dose of the selective FAAH inhibitor PF‐04457845 demonstrated clinical efficacy in patients suffering from cannabis use disorder (CUD) in terms of reduced cannabis withdrawal symptoms, cannabis use, and sleep disturbances 17. This dose had been previously shown to be more than sufficient to result in 97% inhibition of WBC FAAH and elevate plasma FAAs 18. Dose ranging was not done, so these clinical results can only suggest that complete inhibition of FAAH is necessary for efficacy, at least in CUD.…”

Blocking of Fatty Acid Amide Hydrolase Activity with PF-04457845 in Human Brain: A Positron Emission Tomography Study with the Novel Radioligand [11C]CURB

“…Subjects were reminded to have a light meal in the morning and a light lunch was permitted between the scans as food is known to have little effect on overall PF-04457845 pharmacokinetics. 25 …”

“…PF-04457845 is a highly potent (IC 50 = 7.2 nmol/L, with k inact /K i = 40,300/M/s, where k inact is the first-order rate constant of enzyme inactivation at infinite inhibitor concentration and K i is the inhibitor dissociation constant) 23,24 and highly specific irreversible FAAH inhibitor in vitro and ex vivo based on the extensive preclinical characterization. In human clinical trials, 25 this investigational drug was shown to have good safety and tolerability profile and inhibited FAAH activity in peripheral blood leukocytes (497% at 0.3 mg, p.o.) and increased plasma concentrations of fatty acid amides by 3.5 to 10 fold although its effectiveness and optimal dose regimen in the living human brain is unknown.…”

Chemical Probes of Endocannabinoid Metabolism

“…5A), a FAAH inhibitor with excellent potency, selectivity, oral availability, and efficacy in a rat models of inflammatory and noninflammatory pain (Ahn et al, 2011;Johnson et al, 2011). In phase I trials, PF-04457845 nearly completely inhibited FAAH activity in blood leukocytes, elevated plasma anandamide and other NAE levels 3.5-to 10-fold, and was well tolerated (Li et al, 2012). Recently, however, PF-04457845 failed to show efficacy in Phase II trials in patients with osteoarthritic knee pain .…”