Steady-state pharmacokinetics and pharmacodynamics of CHF3381, a novel antineuropathic pain agent, in healthy subjects

Abstract

Aims: To evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic profiles of CHF3381, a dual NMDA and MAO-A inhibitor, after multiple oral doses in healthy subjects.

Methods: Forty-eight young males received CHF3381 at doses of 100 mg twice daily, 200 mg twice daily, 400 mg twice daily or placebo for 2 weeks according to a double-blind, randomized, parallel group design. Plasma and urine concentrations of the parent drug and of two major metabolites (CHF3567 and 2-aminoindane) were measured over time. MAO-A activity in plasma was estimated by measuring plasma concentrations of 3,4-dihydroxyphenylglycol. Sustained attention, memory and sedation were assessed throughout the study with standard psychometric tests.

Results: Most of the adverse events were mild in intensity, with dose regimens of 100 mg twice daily and 200 mg twice daily being indistinguishable from placebo. After 400 mg twice daily, the most frequent adverse events were mild dizziness, asthenia and insomnia. At steady-state, 400 mg twice daily slightly increased supine heart rate (+ 9 +/- 2 beats min(-1)) and diastolic blood pressure (+6 +/- 2 mmHg) compared with placebo. There were no dose-dependent or consistent effects of CHF3381 on attention, motor co-ordination or memory, but 400 mg twice daily significantly decreased alertness compared with placebo. Plasma concentrations of CHF3381 peaked at around 3 h and were dose-proportional. The elimination half-life of CHF3381 was estimated to be 4-6 h. At steady-state, significant CHF3381 plasma concentrations were detected at predose with a modest accumulation (1.3-1.5 times), showing that the drug given twice daily is active over the entire 24 h period. Plasma concentrations of CHF3567 and of 2-aminoindane were also proportional to the dose of CHF3381. CHF3381 dose-dependently inhibited MAO-A activity with peak effects at steady-state of 27 +/- 4%, 46 +/- 2% and 65 +/- 5% after 100 mg twice daily, 200 mg twice daily and 400 mg twice daily, respectively. There were no significant effects of CHF3381 on attention (rapid visual information processing), motor co-ordination (body sway) or memory (learning memory task) at any of the doses. At steady-state, there was a significant decrease in alertness (Bond & Lader visual analogue scale) in the 400 mg twice daily group compared with placebo.

Conclusions: A twice daily regimen of CHF3381 appears to be adequate from a pharmacokinetic and pharmacodynamic perspective. Plasma concentrations reached with 400 mg twice daily exceeded those observed in animals receiving pharmacologically active doses in chronic pain models.

Figure 1

The major metabolic pathways for CHF3381

Figure 2

Mean (± SEM) plasma concentrations of CHF3381 (panel a), CHF3567 (panel b) and 2-aminoindane (panel c) measured after the first (open symbols) and the last dose (closed symbols) of 100 mg twice daily (circles), 200 mg twice daily (squares) or 400 mg twice daily (triangles) of CHF3381 in young healthy males

Figure 3

Inhibition of MAO-A after placebo and different dose regimens of CHF3381 in young healthy males at steady state. Placebo bid (n = 12) (○), 100 mg bid (n = 12) (•), 200 mg bid (n = 12) (▪), 400 mg bid (n = 11) (▾)