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Randomized Controlled Trial
, 73 (5), 706-16

Assessment of the Pharmacology and Tolerability of PF-04457845, an Irreversible Inhibitor of Fatty Acid Amide hydrolase-1, in Healthy Subjects

Affiliations
Randomized Controlled Trial

Assessment of the Pharmacology and Tolerability of PF-04457845, an Irreversible Inhibitor of Fatty Acid Amide hydrolase-1, in Healthy Subjects

Gai Ling Li et al. Br J Clin Pharmacol.

Abstract

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 t(max) 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.

Figures

Figure 1
Figure 1
Mean (SD) PF-04457845 plasma concentrations following single oral doses (SRD study). 0.1 mg (●), 0.3 mg (○), 1 mg (▴), 3 mg (▵), 10 mg (formula image), 20 mg (□), 40 mg (◆)
Figure 2
Figure 2
Mean dose normalized Cmax (●) and AUC(0,∞) (○) vs.dose of PF-04457845 (SRD study)
Figure 3
Figure 3
Mean (SD) PF-04457845 plasma concentrations following once daily oral doses (MRD study). 0.5 mg (●), 1 mg (▵), 4 mg (formula image), 8 mg (◊)
Figure 4
Figure 4
(A) Mean (SD) % inhibition of FAAH1 following single oral doses of PF-04457845 (SRD study). Placebo (★), 0.1 mg (●), 0.3 mg (○), 1 mg (▴), 3 mg (▵), 10 mg (formula image), 20 mg (□), 40 mg (◆). The SDs have been omitted from the placebo line as they were large (average 73%) and obscure the SDs for the active doses. (B) Mean (SD) % inhibition of FAAH1 following once daily oral doses of PF-04457845 (MRD study). Placebo (★), 0.5 mg (●), 1 mg (▵), 4 mg (formula image), 8 mg (◊)
Figure 5
Figure 5
Mean (SD) elevation of AEA (A), LEA (B), OEA (C) and PEA (D) following once daily oral doses of PF-04457845 (MRD study). Placebo (★), 0.5 mg (●), 1 mg (▵), 4 mg (formula image), 8 mg (◊)
Figure 6
Figure 6
The relationship between PF-04457845 plasma concentrations and FAAH1 inhibition at doses up to 10 mg PF-04457845 (SRD study), 0.1 mg (●), 0.3 mg (○), 1 mg (▴), 3 mg (▵), 10 mg (formula image). (Higher doses are entirely compatible with the emergent pattern but are not included as the amount of data at high concentrations obscures the relationship.)
Figure 7
Figure 7
Mean (SE) change from baseline in standardized composite score of the cognitive function tests following once daily oral doses of PF-04457845 (MRD study). Placebo (★), 0.5 mg (●), 1 mg (▵), 4 mg (formula image), 8 mg (◊)

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