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

Abstract

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 develop-ment 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 Ϫ1 ). 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 ⅐ h Ϫ1 , reduced by 63% at maximal CHF3381 concentrations. EC 50 was 1670 g/l, not significantly different from the in vitro IC 50 . The increase in heart rate due to CHF3381 was 0.0055 bpm/g l Ϫ1 . CHF3381 produces a concentration-dependent decrease in DHPG plasma concentrations, whose magnitude increased after multiple twice-a-day regimens for 14 days.

Pharmacodynamics of norepinephrine reuptake inhibition: Modeling the peripheral and central effects of atomoxetine, duloxetine, and edivoxetine on the biomarker 3,4‐dihydroxyphenylglycol in humans

“…It is noted that atomoxetine had the highest dose of the 3 drugs and achieved higher plasma drug concentrations than duloxetine or edivoxetine (see Figure 1), but elicited an effect on plasma DHPG similar to edivoxetine and duloxetine (see Figure 2). The plasma DHPG baseline in this study was similar to that observed in a study using MOA-A inhibitors 28,29 ; however, the maximal plasma DHPG inhibition with monoamine oxidase-A inhibitors was greater (80%) than what we determined for NET inhibitors (33% to 37%). The K out parameter reflects the elimination rate constant for plasma DHPG, and was not expected to be affected by the selection of drug.…”

“…The time course of reduction in plasma and CSF DHPG concentrations was characterized using an indirect response model with inhibition of the production of DHPG (K in ) based on the mechanism of action of NET inhibitors; that is, inhibition of NE reuptake, leading to less intraneuronal metabolism of NE to DHPG, which is reflected in decreases in plasma and CSF DHPG concentrations. The delay in response relative to plasma drug concentration was consistent with the observed anticlockwise hysteresis reported for plasma DHPG in the presence of monoamine oxidase A inhibitors . To note, plasma and CSF NE data were collected across the 3 drugs, but our analysis indicated that DHPG provided a less variable response than NE (data not shown).…”

“…The delay in response relative to plasma drug concentration was consistent with the observed anticlockwise hysteresis reported for plasma DHPG in the presence of monoamine oxidase A inhibitors. 28,29 To note, plasma and CSF NE data were collected across the 3 drugs, but our analysis indicated that DHPG provided a less variable response than NE (data not shown). Therefore, we chose to use DHPG as the biomarker for modeling the effects of the NET inhibitors.…”

Clinical Pharmacology Tyramine Challenge Study to Determine the Selectivity of the Monoamine Oxidase Type B (MAO‐B) Inhibitor Rasagiline

“…Treatment with drugs that inhibit MAO‐A has previously been demonstrated to reduce the plasma concentration of DHPG 24 , 25 , 28 – 30 produced after oxidation of noradrenalin by MAO‐A 31 . Therefore, the plasma level of DHPG was used as an indirect marker of MAO‐A activity (Figure 3).…”

“…Measurement of plasma concentration of dihydroxyphenylglycol (DHPG), a deaminated metabolite of norepinephrine, was used as a crude marker of MAO‐A activity 24 , 25 . For determination of plasma DHPG, 5‐mL blood samples were collected on day 1, before and 2 hours after tyramine administration, and on day 24 (day 40 for group 4b) 0.5 hours after study drug administration.…”