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Pharmacokinetics and Safety Profile of Ispronicline (TC‐1734), a New Brain Nicotinic Receptor Partial Agonist, in Young Healthy Male Volunteers
Author(s) -
Dunbar G.,
Demazières A.,
Monreal A.,
Cisterni C.,
Metzger D.,
Kuchibhatla R.,
Luthringer R.
Publication year - 2006
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270006288730
Subject(s) - tolerability , partial agonist , pharmacokinetics , placebo , agonist , medicine , adverse effect , pharmacology , nicotine , nicotinic agonist , crossover study , anesthesia , receptor , pathology , alternative medicine
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 α4β2 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, × 10 days). C max of TC‐1734 was reached around 1 to 2 hours postdose, and mean terminal half‐life (t 1/2 ) 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.