title: Pharmacokinetics and pharmacodynamics of CHF5074 after short-term administration in healthy subjects.
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.
authors.affiliation: Research & Development, Chiesi Pharmaceuticals Inc., Rockville, MD, USA. b.imbimbo@chiesigroup.com
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Imbimbo
authors.forename: Enrico
authors.initials: E
authors.lastname: Frigerio
authors.forename: Massimo
authors.initials: M
authors.lastname: Breda
authors.forename: Francesco
authors.initials: F
authors.lastname: Fiorentini
authors.forename: Mercedes
authors.initials: M
authors.lastname: Fernandez
authors.forename: Sandra
authors.initials: S
authors.lastname: Sivilia
authors.forename: Luciana
authors.initials: L
authors.lastname: Giardino
authors.forename: Laura
authors.initials: L
authors.lastname: Calzà
authors.forename: Dottie
authors.initials: D
authors.lastname: Norris
authors.forename: Daniela
authors.initials: D
authors.lastname: Casula
authors.forename: Magdy
authors.initials: M
authors.lastname: Shenouda
mesh_terms: D000328:Adult; D003521:Cyclopropanes / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D005480:Flurbiprofen / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: C522246:1-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid; D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D005480:Flurbiprofen