Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP3652, a Reversible Fatty Acid Amide Hydrolase Inhibitor, in Healthy, Nonelderly, Japanese Men and Elderly, Japanese Men and Women: A Randomized, Double-blind, Placebo-controlled, Single and Multiple Oral Dose, Phase I Study

Purpose: This study aimed to evaluate the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of ASP3652, a peripherally acting inhibitor of peripheral fatty acid amide hydrolase (FAAH) after 30-, 100-, 300-, 600-, and 900-mg single and 100- and 300-mg BID multiple oral dose in Japanese patients. Methods: This was a randomized, double-blind, placebo-controlled, single and multiple oral dose Phase I study in healthy, nonelderly men and elderly men and women. The study consisted of 2 parts: in the single oral dose part, 40 healthy, nonelderly men were randomized to receive placebo or ASP3652; in the multiple oral dose part, 48 enrolled nonelderly men and elderly men and women were randomized to receive placebo or ASP3652. In both parts, the investigator judged whether the individuals were healthy based on the results of physical examinations and screening. The safety profile was assessed by examining adverse events, defined as any untoward medical occurrence in an individual administered the study drug and that did not necessarily have a causal relationship with the study treatment; clinical laboratory evaluations; vital signs; the Profile of Mood States scale; and standard 12-lead ECGs and 12-lead ECGs for QT assessment. Pharmacokinetic parameters were estimated using unchanged ASP3652 concentrations in plasma and urine. Pharmacodynamic parameters were estimated using FAAH activity and plasma anandamide, oleoylethanolamide, and palmitoylethanolamide concentrations. Safety and tolerability profiles were compared with the placebo group. Findings: ASP3652 was rapidly absorbed to reach C-max in a single dose and near steady-state at approximately 3 days after the start of multiple dosing. The C-max and AUC of ASP3652 were slightly higher than dose proportional after a single dose of ASP3652 at 30-900 mg. There was no apparent accumulation based on C max and AUC(0-)(12) after multiple doses. Although no differences were found in C max or AUC(0)(-)(12) by age in men, C-max and AUC(0-)(12) were slightly higher in elderly women than elderly men. FAAH activity was inhibited in a dose-dependent manner, and plasma levels of anandamide, oleoylethanolamide, and palmitoylethanolamide increased in all dose groups after single and multiple doses of ASP3652. The incidence of adverse events after multiple doses, which ranged from 44.4% to 66.7%, was similar across all treatment groups, including the placebo group. (C) 2020 Elsevier Inc.