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Safety, Pharmacokinetics, and Pharmacodynamics of CHF 3381, a Novel N-Methyl-D-Aspartate Antagonist, after Single Oral Doses in Healthy Subjects

From Biotrial, Technopole Atalante Villejean, Rennes, France (Dr. Tarral, Dr. Dostert, Mr. Guillevic) and the Research & Development Department, Chiesi Farmaceutici, Parma, Italy (Dr. Fabbri, Dr. Rondelli, Dr. Mariotti, Dr. Imbimbo).

A double-blind, randomized, placebo-controlled study was performed to assess the safety, tolerability, and pharmacokinetics of single oral doses of CHF 3381 in 56 young healthy male volunteers. The central nervous system effects of CHF 3381 were also evaluated, as well as the effect of food on the rate and extent of CHF 3381 absorption. Seven doses of CHF 3381 (25, 50, 100, 200, 300, 450, and 600 mg) were evaluated in an escalating order. At each dose level, 6 subjects were given CHF 3381, and 2 subjects were given placebo. Safety and tolerability evaluation included adverse events, physical examination, vital functions, electrocardiogram, laboratory tests, and 24-hour Holter (100-mg and 450-mg dose panels). Plasma and urinary concentrations of CHF 3381 and its two main metabolites (CHF 3567 and 2-aminoindane) were measured with a validated high-performance liquid chromatography method. Central nervous system effects were evaluated with the simple reaction time (SRT); learning memory task (LMT); Bond & Lader Visual Analog Scale for alertness, contentedness, and calmness; Addiction Research Center Inventory (ARCI); and electroencephalogram. There were no serious adverse events; the most frequent adverse events were dizziness, abnormal thinking, and asthenia. The number of adverse events with moderate intensity increased sharply with the dose, with no or few events up to 450 mg and 17 events with 600 mg. Therefore, 600 mg was defined as the maximum tolerated dose. There were no significant treatment effects on cardiovascular function and electrocardiogram parameters at any CHF 3381 dose or on oral temperature or laboratory tests. There were no clinically significant changes in laboratory variables. CHF 3381 was absorbed rapidly (t_max = 0.5-2 h) and cleared from plasma with a half-life of 3 to 4 hours. Plasma levels of CHF 3381 and its two major metabolites were found to be proportional to the dose. 2-Aminoindane formed slowly and reached much lower concentrations compared to the parent compound and the other metabolite (CHF 3567). Within 48 hours after dosing, 2% to 6% of the administered dose was found in the urine as unchanged drug, about 50% to 55% as the acid derivative (CHF 3567), and 2% to 3% as 2-aminoindane. Ingestion of food did not affect the extent of absorption of the drug, while the rate of absorption was considerably reduced (t_max = 4 h). No significant effects of CHF 3381 were observed on attention (SRT) or memory (LMT). Visual analog scales revealed a decreasing effect of CHF 3381 on alertness at 1 hour that reached statistical significance at 300 and 600 mg. EEG spectral analysis revealed minor decreasing effects of the 200-mg dose on total electric power measured at 2 hours. A stimulant effect was detected by the ARCI scale 24 hours after the 300-mg dose and might be related to the slow formation of the 2-aminoindane metabolite. In conclusion, this study has shown that the maximum tolerated dose of CHF 3381 after single oral administration in young healthy male volunteers is 600 mg. CHF 3381 displays linear pharmacokinetics in the dose range of 25 to 600 mg. The compound is rapidly absorbed and cleared from plasma with a half-life of 3 to 4 hours. The ingestion of food seems to not affect the extent of absorption of the drug. Minor effects on the central nervous system were detected at doses equal to or greater than 300 mg.

Key Words: CHF 3381 • NMDA receptor antagonists • neuropathic pain • pharmacokinetics • pharmacodynamics

Address for reprints: Dr. Bruno P. Imbimbo, Research & Development Department, Chiesi Farmaceutici, Via Palermo 26/A, 43100 Parma, Italy.