RT Journal Article
SR Electronic
T1 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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 647
OP 657
DO 10.1124/jpet.104.080457
VO 313
IS 2
A1 Chantal Csajka
A1 Bruno P. Imbimbo
A1 Annalisa Piccinno
A1 Philippe Dostert
A1 Davide Verotta
YR 2005
UL http://jpet.aspetjournals.org/content/313/2/647.abstract
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