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Pharmacokinetics and Safety Profile of Ispronicline (TC-1734), a New Brain Nicotinic Receptor Partial Agonist, in Young Healthy Male Volunteers

From FORENAP, Rouffach, France (Demazières, Monreal, Cisterni, Metzger, Luthringer) and TARGACEPT, Winston-Salem, North Carolina (Dunbar, Kuchibhatla).

Recent research suggests that drugs activating nicotine acetylcholine receptors might be promising therapy in cognitive decline seen in the elderly, including Alzheimer's disease. Ispronicline (TC-1734), a brain-selective 4ß2 nicotine acetylcholine receptor partial agonist, has shown memory-enhancing properties in rodents and a good tolerability profile. The safety and the full pharmacokinetic profile of TC-1734 and its N-desalkylated metabolite, TC-1784, were investigated in 2 phase I studies, and results are reported in this article. Study A used a double-blind, placebo-controlled, crossover design with a rising single-dose scheme (2-320 mg). Study B used a double-blind, placebo-controlled, parallel-group design with a rising multiple-dose scheme (doses: 50, 100, and 200 mg, once daily, x 10 days). C_max of TC-1734 was reached around 1 to 2 hours postdose, and mean terminal half-life (t) ranged from 3 to 5.3 hours (single doses) and from 2.7 to 8.8 hours (repeated doses). No accumulation of TC-1734 was observed after 10 days. Renal clearance appeared to be a minor method of elimination of TC-1734 and TC-1784. A high interindividual variability was noted for all parameters. Across the dose ranges explored, TC-1734 was safe and well tolerated. No changes of clinical significance were seen on laboratory and cardiovascular parameters. Adverse events were generally of mild to moderate intensity, with dizziness and headache being reported most frequently.

Key Words: Alzheimer • ispronicline • nicotine acetylcholine receptor (nAChR) • phase I

Address for reprints: A. Demazières, FORENAP, 27 rue du 4° RSM, 68250 Rouffach, France; e-mail: agnes.demazieres{at}forenap.asso.fr.

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