Safety, Tolerability, Pharmacokinetics, and Aβ 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.

Disease-modifying treatments for Alzheimer’s disease

“…No significant changes in Ab42 CSF levels were shown after treatment. However, higher drug concentrations in plasma were related to statistically significantly lower Ab levels [Galasko et al 2007]. …”

Initial Optimization of a New Series of γ-Secretase Modulators Derived from a Triterpene Glycoside

“…28,29 A representative example is (R)-flurbiprofen, which advanced to clinical trials but failed due to lack of potency and poor brain exposure, a common problem among the NSAID GSMs. 30,31 There have been more recent disclosures of carboxylic acid GSMs and aryl imidazole GSMs which more potently reduce levels of Aβ42 while raising levels of Aβ38. 22,23 A recent report of three distinct pyrimidine-based GSMs showed reduction of both Aβ40 and Aβ42 in vitro but different effects on Aβ(37− 39), with some examples raising Aβ38 and some having no effect on Aβ38 production.…”

New Perspectives for the Treatment of Alzheimer’s Disease~!2008-10-07~!2008-10-30~!2008-11-26~!

“…No significant changes of A 42 CSF levels were shown after treatment. However, in plasma, higher drug concentrations were related to statistically significant lower A levels [41].…”