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 (t(1/2z)=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% of the parent compound. Drug levels in the CSF were dose-proportional. The drug dose-dependently lowered the levels of the soluble CD40 ligand, a marker of microglia activation, in both plasma and CSF samples.

Bruno P. Imbimbo, Enrico Frigerio, Massimo Breda, Francesco Fiorentini, Mercedes Fernandez, Sandra Sivilia, et al. (2013). Pharmacokinetics and Pharmacodynamics of CHF5074 After Short-term Administration in Healthy Subjects. ALZHEIMER DISEASE & ASSOCIATED DISORDERS, 27(3), 278-286 [10.1097/WAD.0b013e3182622ace].

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

FERNANDEZ CANALES, MARIA DE LAS MERCEDES;SIVILIA, SANDRA;GIARDINO, LUCIANA;CALZA', LAURA;
2013

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 (t(1/2z)=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% of the parent compound. Drug levels in the CSF were dose-proportional. The drug dose-dependently lowered the levels of the soluble CD40 ligand, a marker of microglia activation, in both plasma and CSF samples.
2013
Bruno P. Imbimbo, Enrico Frigerio, Massimo Breda, Francesco Fiorentini, Mercedes Fernandez, Sandra Sivilia, et al. (2013). Pharmacokinetics and Pharmacodynamics of CHF5074 After Short-term Administration in Healthy Subjects. ALZHEIMER DISEASE & ASSOCIATED DISORDERS, 27(3), 278-286 [10.1097/WAD.0b013e3182622ace].
Bruno P. Imbimbo;Enrico Frigerio;Massimo Breda;Francesco Fiorentini;Mercedes Fernandez;Sandra Sivilia;Luciana Giardino;Laura Calzà;Dottie Norris;Daniela Casula;Magdy Shenouda
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/214690
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