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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Mechanistic Pharmacokinetic and Pharmacodynamic Modeling of CHF3381 (2-[(2,3-Dihydro-1H-inden-2-yl)amino]acetamide Monohydrochloride), a Novel N-Methyl-D-aspartate Antagonist and Monoamine Oxidase-A Inhibitor in Healthy Subjects

Departments of Biopharmaceutical Sciences (C.C., D.V.) and Biostatistics (D.V.), University of California, San Francisco, California; Research & Development Department, Chiesi Farmaceutici, Parma, Italy (B.P.I., A.P.); and Biotrial, Technopole Atalante Villejean, rue Jean-Louis Bertrand, Rennes, France (P.D.)

CHF3381 (2-[(2,3-dihydro-1H-inden-2-yl)amino]acetamide monohydrochloride) is a new N-methyl-D-aspartate antagonist and reversible monoamine oxidase-A (MAO-A) inhibitor in development for the treatment of neuropathic pain. This study developed a mechanistic model to describe the pharmacokinetics of CHF3381 and of its two metabolites, the relationship with MAO-A activity and heart rate. Doses of 100, 200, and 400 mg twice daily for 2 weeks were administered orally to 36 subjects. MAO-A activity was estimated by measuring concentrations of 3,4-dihydroxyphenylglycol (DHPG), a stable metabolite of norepinephrine. A multicompartment model with time-dependent clearance was used to describe the kinetics of CHF3381 and metabolite concentrations. Estimated pharmacokinetic parameters were CL (41.2 to 27.4 l/h over the study), V (131 liters), Q (1.7 l/h), V_p (36 liters), and k_a (1.85 h^–1). The relationship between CHF3381 and DHPG or heart rate was described using an indirect or a direct linear model, respectively. The production rate of DHPG (k_in) was 2540 ng · h^–1, reduced by 63% at maximal CHF3381 concentrations. EC₅₀ was 1670 µg/l, not significantly different from the in vitro IC₅₀. The increase in heart rate due to CHF3381 was 0.0055 bpm/µ^{g l–1}. CHF3381 produces a concentration-dependent decrease in DHPG plasma concentrations, whose magnitude increased after multiple twice-a-day regimens for 14 days.

Address correspondence to: Dr. Davide Verotta, Department of Biopharmaceutical Sciences and Biostatistics, University of California, Box 0446, San Francisco, CA 94143. E-mail: davide{at}ariel1.ucsf.edu