The Safety and Tolerance of Xanomeline Tartrate, an M1-Specific Cholinergic Agonist, in Patients with Alzheimer’s Disease
Xanomeline tartrate [3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-l-methylpyridine tartrate], also known as LY246708 tartrate, is a potent and selective M1 agonist that crosses the blood brain barrier in animals and is orally bioavailable (Eli Lilly, unpublished data). Safety trials of xanomeline tartrate in healthy young adults did not determine a maximum tolerated dose. At the highest dose tested in a single dose trial, 150 mg, one volunteer experienced moderate nausea, while no adverse effects were observed at doses up to 75 mg bid in a multiple dose trial. A study of healthy elderly subjects reported moderate diarrhea, nausea, vomiting, diaphoresis and hypotension at the maximum dose of 50 mg tid. However, higher dosages were not tested. Clinical trials of other cholinergic compounds have shown that the AD patient population frequently tolerates drugs quite differently from healthy volunteers (Cutler et al., 1992). “Bridging studies” which determine the safety and tolerance of a drug in the target population aid in the selection of appropriate doses for Phase II efficacy tests (Cutler et al., 1993). We report the results of two double-blind, placebo controlled bridging studies of the safety and tolerance of xanomeline tartrate in AD patients.
KeywordsCholinergic Agonist Healthy Elderly Subject Orthostatic Blood Pressure Moderate Nausea Moderate Diarrhea
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