Tolerability, pharmacokinetic and pharmacodynamic profile of BIA 10-2474 in healthy volunteers following multiple ascending doses

F. Rocha1, A. Santos1, D. Chassard2, A. Patat2, B. Astruc2, A. Falcão3, H. Gama1, P. Soares-da-Silva1,4,. 1Dept. Research & Development, BIAL – Portela & Cª, S.A., 4745-457 Coronado (S. Romão e S. Mamede), PORTUGAL, 2Biotrial, Rennes, FRANCE, 3Dept. Pharmacology, Faculty of Pharmacy, University Coimbra, Coimbra, PORTUGAL, 4Dept. Pharmacology & Therapeutics, Faculty of Medicine, University Porto, Porto, PORTUGAL.

Introduction: BIA 10-2474 (3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide) is a novel FAAH inhibitor developed by BIAL for the treatment of medical conditions in which there is an advantage in enhancing the levels of endogenous anandamide (AEA) and tonically increasing the drive of the endocannabinoid system. This study was designed to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending dose (MAD) administrations of BIA 10-2474 in healthy human subjects.

Methods: The sequential ascending-dose placebo-controlled double-blind design was used for a safe determination of the maximum tolerated dose and the establishment of a sufficient safety margin over the expected therapeutic doses in humans. The MAD part consisted of 5 cohorts of 8 healthy subjects, gender balanced to the extent possible, each receiving 10 once-daily administrations of BIA 10-2474 or placebo (6 active and 2 placebos). The MAD dose range was from 2.5 to 50mg. The study was terminated early during the 50mg BIA 10-2474 dose-group due to a severe unexpected CNS treatment-emergent-adverse-event (TEAE). Therefore, only safety up to 20mg is presented.

Results: Overall, 32 subjects aged between 22 and 53 years were randomized (8 to placebo and 24 to BIA 10-2474) and all completed the MAD-part up to 20mg. No serious adverse-event (AE) or important medical event was reported. No withdrawal due to AEs occurred. Twelve (12) TEAEs of mild (n=11) or moderate (n=1) severity were observed in 9 subjects. Eight were considered possibly related. Among all TEAEs, 3 were gastrointestinal-disorders (abdominal pain in 2 subjects, liquid stool in 1), 2 CNS disorders (headache), 2 eye disorders (blurred vision), 2 infections (cold), 2 vascular disorders (dizziness, orthostatic dizziness) and 1 was left sciatalgia. No dose-effect was observed in TEAE occurrence or severity. Over the range 2.5 to 50mg BIA 10-2474, there was an approximately dose-proportional increase for Cmax and AUC0-τ on Days 1 and 10 (no data for 50mg). BIA 10-2474 metabolites assessed presented a negligible contribution for the overall kinetic evaluation. On Day 10, the extent of AEA systemic exposure increased in a dose dependent manner up to 20mg BIA 10-2474.

Conclusions: Following multiple-ascending-doses up to 20mg, BIA 10-2474 was found to be safe and well tolerated and systemic exposure to AEA increased in a dose dependent manner.