PT - JOURNAL ARTICLE AU - Chantal Csajka AU - Bruno P. Imbimbo AU - Annalisa Piccinno AU - Philippe Dostert AU - Davide Verotta TI - Mechanistic Pharmacokinetic and Pharmacodynamic Modeling of CHF3381 (2-[(2,3-Dihydro-1<em>H</em>-inden-2-yl)amino]acetamide Monohydrochloride), a Novel <em>N</em>-Methyl-<span class="sc">d</span>-aspartate Antagonist and Monoamine Oxidase-A Inhibitor in Healthy Subjects AID - 10.1124/jpet.104.080457 DP - 2005 May 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 647--657 VI - 313 IP - 2 4099 - http://jpet.aspetjournals.org/content/313/2/647.short 4100 - http://jpet.aspetjournals.org/content/313/2/647.full SO - J Pharmacol Exp Ther2005 May 01; 313 AB - 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), Vp (36 liters), and ka (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 (kin) 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/μg l–1. CHF3381 produces a concentration-dependent decrease in DHPG plasma concentrations, whose magnitude increased after multiple twice-a-day regimens for 14 days. The American Society for Pharmacology and Experimental Therapeutics