title: Safety, tolerability, pharmacokinetics, and Abeta levels after short-term administration of R-flurbiprofen in healthy elderly individuals.
abstract: To evaluate the safety and tolerability and pharmacokinetic properties of R-flurbiprofen (Tarenflurbil) in normal elderly individuals and to determine the effect of the drug on amyloid beta 42 (Abeta42) levels, we conducted a double-blind, placebo-controlled study of 48 healthy subjects aged 55 to 80. Three successive cohorts were randomized to doses of 400, 800, or 1600 mg/d, or placebo, given as 2 divided doses for 21 days. Blood and cerebrospinal fluid were collected for pharmacokinetic studies and measurement of Abeta levels at baseline and on day 21. R-flurbiprofen was well-tolerated at all 3 doses. The compound penetrated the blood-brain barrier in a dose-dependent manner. From baseline to 21 days, comparisons between study groups revealed no significant differences in changes of cerebrospinal fluid Abeta42 levels and no significant differences in changes of plasma Abeta42 levels at the time of trough drug level at 21 days of treatment. Further analysis of drug concentration-response for plasma samples showed that at the time of peak plasma concentration, higher plasma drug concentration was related to lower Abeta42 plasma levels (P=0.016). R-flurbiprofen had an excellent safety profile and showed dose-dependent central nervous system penetration. Exploratory analyses of plasma Abeta and peak drug levels suggested a short-term effect in plasma that warrants independent verification. The safety, tolerability, and pharmacokinetic profile of R-flurbiprofen in these older individuals support the ongoing studies of this compound in patients with Alzheimer disease.
authors: Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA. dgalasko@ucsd.edu
authors: Douglas R
authors: DR
authors: Galasko
authors: Neil
authors: N
authors: Graff-Radford
authors: Susanne
authors: S
authors: May
authors: Suzanne
authors: S
authors: Hendrix
authors: Barbara A
authors: BA
authors: Cottrell
authors: Sarah A
authors: SA
authors: Sagi
authors: Gary
authors: G
authors: Mather
authors: Mark
authors: M
authors: Laughlin
authors: Kenton H
authors: KH
authors: Zavitz
authors: Edward
authors: E
authors: Swabb
authors: Todd E
authors: TE
authors: Golde
authors: Michael P
authors: MP
authors: Murphy
authors: Edward H
authors: EH
authors: Koo
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid / Q000187:drug effects*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000032:analysis / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005480:Flurbiprofen / Q000009:adverse effects* / Q000032:analysis / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013995:Time
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005480:Flurbiprofen