title: Pharmacokinetics and safety profile of ispronicline (TC-1734), a new brain nicotinic receptor partial agonist, in young healthy male volunteers.
abstract: 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 alpha4beta2 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). Cmax of TC-1734 was reached around 1 to 2 hours postdose, and mean terminal half-life (t1/2) 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.
authors.affiliation: TARGACEPT, Winston-Salem, North Carolina, USA.
authors.forename: G
authors.initials: G
authors.lastname: Dunbar
authors.forename: A
authors.initials: A
authors.lastname: Demazières
authors.forename: A
authors.initials: A
authors.lastname: Monreal
authors.forename: C
authors.initials: C
authors.lastname: Cisterni
authors.forename: D
authors.initials: D
authors.lastname: Metzger
authors.forename: R
authors.initials: R
authors.lastname: Kuchibhatla
authors.forename: R
authors.initials: R
authors.lastname: Luthringer
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004311:Double-Blind Method; D006801:Humans; D008297:Male; D008875:Middle Aged; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D012016:Reference Values
chemical_list: D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; C490152:ispronicline