Pharmacokinetics and Pharmacodynamics of CHF5074 After Short-term Administration in Healthy Subjects.

Pharmacokinetics and Pharmacodynamics of CHF5074 After Short-term Administration in Healthy Subjects. Alzheimer Dis Assoc Disord. 2012 Aug 23; Authors: Imbimbo BP, Frigerio E, Breda M, Fiorentini F, Fernandez M, Sivilia S, Giardino L, Calzà L, Norris D, Casula D, Shenouda M Abstract CHF5074 has been shown to inhibit brain β-amyloid deposition and attenuate memory deficits in different transgenic mice models of Alzheimer disease. We evaluated the safety, pharmacokinetics, and pharmacodynamics of 3 ascending dose regimens of CHF5074 (200, 400, and 600 mg/d for 14 d) in a double-blind, placebo-controlled, parallel group study involving 48 healthy subjects. Plasma, urine, and cerebrospinal fluid (CSF) samples were collected for measuring drug and main metabolite concentrations and potential biomarkers of pharmacodynamic activity (β-amyloid1-40, β-amyloid1-42, soluble CD40 ligand, and tumor necrosis factor-α). All subjects completed the study, and no serious or severe adverse events were reported. The maximum tolerated dose was close to 600 mg/d with mild diarrhea being the most frequent adverse event at this dose. CHF5074 reached peak plasma levels 2 to 3 hours after drug administration and then was slowly eliminated (t1/2z=30 h) in the urine as glucoronide. Systemic exposure to the drug appeared to be dose-proportional with a 2-fold accumulation ratio at steady state. Metabolite plasma levels peaked at 4 to 5 hours and accounted for about 25...
Source: Alzheimer Disease and Associated Disorders - Category: Psychiatry Tags: Alzheimer Dis Assoc Disord Source Type: research