Received for publication November 10, 2004.
Revised January 14, 2005.
Accepted for publication January 18, 2005.

Mechanistic Pharmacokinetic and Pharmacodynamic Modeling of CHF3381, a Novel NMDA Antagonist and MAO-A Inhibitor in Healthy Subjects

Abstract

CHF3381 is a new N-methyl-D-aspartate antagonist (NMDA)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 mg, 200 mg and 400 mg twice daily for two 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 multi-compartment model with time-dependent clearance was used to describe the kinetics of CHF3381 and metabolites concentrations. Estimated pharmacokinetic parameters were CL (43.0 L/h to 27.5 L/h over the study), V (133 L), Q (1.7 L/h), V_p (40 L) and ka (1.86 h^-1). The relationship between CHF3381 and DHPG or heart rate was described using an indirect or a direct linear model, respectively. An in vitro/in vivo correlation for DHPG was established using an estimate of in vitro IC50 as a Bayesian prior. The production rate of DHPG (kin) was 2540 ng/h^-1, reduced by 63% at maximal CHF3381 concentrations. EC50 was 1,670 µg/L, not significantly different from 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.

Key words: CHF3381, MAO-A inhibitor, Pharmacodynamics, Pharmacokinetics, Population, modeling