Safety, Tolerability, and Pharmacokinetics of FAAH Inhibitor BIA 10-2474: A Double-Blind, Randomized, Placebo-Controlled Study in Healthy Volunteers

Abstract

This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of BIA 10-2474, a fatty acid amide hydrolase (FAAH) inhibitor, after first administration to healthy male and female participants. Participants (n = 116) were recruited into this phase I, double-blind, randomized, placebo-controlled, single ascending dose and multiple ascending dose (10-day) study. The primary outcome was the safety and tolerability of BIA 10-2474. Secondary outcomes were pharmacokinetics of BIA 10-2474 and pharmacodynamics, considering plasma concentrations of anandamide and three other fatty acid amides (FAAs) and leukocyte FAAH activity. Single oral doses of 0.25-100 mg and repeated oral doses of 2.5-50 mg were evaluated. BIA 10-2474 was well tolerated up to 100 mg as a single dose and up to 20 mg once daily for 10 days. In the cohort receiving repeated administrations of 50 mg, there were central nervous system adverse events in five of six participants, one with fatal outcome, which led to early termination of the study. BIA 10-2474 showed a linear relationship between dose and area under plasma concentration-time curve (AUC) across the entire dose range and reached steady state within 5-6 days of administration, with an accumulation ratio, based on AUC_0-24h , of <2 on Day 10. BIA 10-2474 was rapidly absorbed with a mean terminal elimination half-life of 8-10 hours (Day 10). BIA 10-2474 caused reversible, dose-related increases in plasma FAAs. In conclusion, we propose that these data, as well as the additional data generated since the clinical trial was stopped, do not provide a complete mechanistic explanation for the tragic fatality.

Figure 1

BIA 10‐2474 mean plasma concentrations after (a and b) single and (c and d) multiple oral dose administration. The inset represents concentrations up to 24 hours and dose levels from 0.25 to 40 mg. Panels (e) and (f) depict BIA 10‐2474 plasma concentrations after single oral dose administration of 50 mg BIA 10‐2474 in six participants during Day 1 of the multiple administration period. Plasma concentrations from Days 4 to 8 are predose (C_trough) estimates. Symbols represent the means of six determinations per group. C_trough, lowest concentration.

Figure 2

AEA mean plasma concentrations (a) and after FAAH activity (b) single oral dose administration (SAD part) and AEA mean plasma concentrations after (c) repeated oral dose administration (MAD part). Relationship between BIA 10‐2474 dose and fatty acid amides (FAAs) concentrations: The sigmoidal line of best fit is shown for each FAA ((d), SAD data only; (e), SAD enriched with Day 1 MAD data). Symbols represent the means of six determinations per group. AEA, N‐arachidonyl ethanolamide; AUC, area under plasma concentration‐time curve; FAAH, Fatty acid amide hydrolase; LEA, N‐linoleoyl ethanolamide; OEA, N‐oleoyl ethanolamide; PEA, N‐palmitoyl ethanolamide; PLC, placebo.