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.
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.
Csajka
Chantal
C
Department of Biopharmaceutical Sciences and Biostatistics, University of California, San Francisco, 94143, USA.
Imbimbo
Bruno P
BP
Piccinno
Annalisa
A
Dostert
Philippe
P
Verotta
Davide
D
D000328:Adult; D001499:Bayes Theorem; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007189:Indans / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000097:blood; D008995:Monoamine Oxidase / Q000502:physiology*; D008996:Monoamine Oxidase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology
D018691:Excitatory Amino Acid Antagonists; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D008734:Methoxyhydroxyphenylglycol; D008995:Monoamine Oxidase; D005998:Glycine; C010117:3,4-dihydroxyphenylglycol; C431890:indantadol