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

Détails

ID Serval
serval:BIB_423B7AE184BE
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
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
Périodique
Journal of Pharmacology and Experimental Therapeutics
Auteur(s)
Csajka  C., Imbimbo  B. P., Piccinno  A., Dostert  P., Verotta  D.
ISSN
0022-3565 (Print)
Statut éditorial
Publié
Date de publication
05/2005
Volume
313
Numéro
2
Pages
647-57
Notes
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: May
Résumé
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. EC(50) was 1670 mug/l, not significantly different from the in vitro IC(50). The increase in heart rate due to CHF3381 was 0.0055 bpm/micro(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.
Mots-clé
Adult Bayes Theorem Excitatory Amino Acid Antagonists/*pharmacokinetics/pharmacology Glycine/*analogs & derivatives/*pharmacokinetics/pharmacology Heart Rate/drug effects/physiology Humans Indans/*pharmacokinetics/pharmacology Male Methoxyhydroxyphenylglycol/*analogs & derivatives/antagonists & inhibitors/blood Monoamine Oxidase/*physiology Monoamine Oxidase Inhibitors/*pharmacokinetics/pharmacology Receptors, N-Methyl-D-Aspartate/*antagonists & inhibitors/physiology
Pubmed
Web of science
Création de la notice
25/01/2008 10:48
Dernière modification de la notice
20/08/2019 13:44
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