P4–268: Pharmacokinetics and pharmacodynamics of CHF5022 and CHF5074, two new β–amyloid1–42 lowering agents, after multiple doses in TG2576 transgenic mice

Long–term use of non–steroidal anti–inflammatory drugs (NSAIDs) may delay or prevent the onset of AD. A subset of NSAIDs, including flurbiprofen, has been shown to selectively inhibit the production of β–amyloid1–42 (Aβ42), independently from their cyclooxygenase (COX) inhibiting activity. CHF5022 and CHF5074 are two new flurbiprofen analogues with potent and selective inhibitory activity on Aβ42 and devoid of anti–COX activity. To evaluate the pharmacokinetics and pharmacodynamics of CHF5022 and CHF5074 after multiple dosing in a transgenic mice model of AD (Tg2576). Tg2576 mice were treated with CHF5022 or CHF5074 up to 4–weeks. Drugs were administered either by oral gavage (up to 300 mg/kg/day) or by medicated diet (375 ppm). R–flurbiprofen was used as comparator. R–flurbiprofen was poorly tolerated both at the dose of 25 mg/kg/day by oral gavage for 1 week and in the diet for 4 weeks (32 mg/kg/day) with 25–55% of animals dying during the first days of treatment. CHF5022 and CHF5074 were well tolerated after both oral dosing (up to 300 mg/kg/day) and after medicated diet (50–60 mg/kg/day) with body weight and mortality being similar to controls. CHF5022 and CHF5074 plasma and brain levels were found to increase with the dose. After 5 days of oral gavage, CHF5022 and CHF5074 brain levels at 3 hours were 11% and 5% of corresponding plasma concentrations. After 4 weeks in the diet, CHF5022 reached mean plasma concentrations at 3 hours of 9403 μg/mL in plasma and 294 μg/g in brain, levels 15–20 times higher than those reached with R–flurbiprofen. Plasma Aβ42 concentrations were dose–dependently suppressed by CHF5022 and CHF5074. Brain Aβ42, but not Aβ40, concentrations tended to inversely correlate with brain CHF5022 levels. In Tg2576 mice, multiple doses of CHF5022 and CHF5074 appeared to be better tolerated than R–flurbiprofen. The two drugs showed much higher systemic exposure and brain penetration than R–flurbiprofen. We collected encouraging evidences of in vivo pharmacological activity of CHF5022 and CHF5074 after short–term administration in a transgenic mouse model of AD. The effects of long–term administration of CHF5022 and CHF5074 on cerebral Aβ pathology in transgenic mice are being assessed.