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- W2082264107 abstract "Cleavage of amyloid precursor protein by BACE1 results in the formation of C99, which is further processed into beta amyloid (Aβ) by gamma secretase. Animal models that reliably predict the clinical potency of potential BACE1 inhibitors are sought in order to develop compounds that effectively reduce cerebrospinal fluid (CSF) Aβ concentrations, which according to the amyloid hypothesis may slow Alzheimer's disease progression. Herein, we compare the CSF IC 50 concentrations for two BACE1 inhibitors that were evaluated in dogs and healthy human volunteers (HVs). In single dose studies conducted in dogs (n=6/group), serial CSF samples were obtained via spinal cannula at baseline and up to 48 hours following oral administration of LY2811376 or LY2886721. In single dose studies conducted in human HVs, serial lumbar CSF samples were obtained via indwelling catheterat baseline and for up to 36 hours following oral administration of placebo, at two dose levels of LY2811376 (n=10 subjects per dose) or two dose levels of LY2886721 (n=4 subjects per dose). Plasma and CSF drug and Aβ concentrations were determined for all subjects. Pharmacokinetic models describing CSF concentrations were developed for each compound/species in NONMEM. An indirect response model was developed to relate CSF drug concentrations to changes in CSF Aβ 1-x (dog studies) or CSF Aβ 1-40 (clinical studies). Plasma pharmacokinetics were described using either a 1- or 2- compartment model for each compound/species. For LY2811376, the CSF IC 50 in dogs was 23.7 ng/mL (6.84% Standard error of the estimate (SEE)) and 27.9 ng/mL in humans (13.3 %SEE). The IC 50 for LY2886721 was 6.14 ng/mL (20.8% SEE) in dogs and 5.06 ng/mL in humans (1.59 %SEE). This work demonstrates that the potency of BACE1 inhibitors in CSF is similar between dogs and humans. The cannulated dog model is useful in preclinical development for estimating clinical exposures necessary for achieving substantial CSF Aβ reduction." @default.
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- W2082264107 date "2014-07-01" @default.
- W2082264107 modified "2023-09-27" @default.
- W2082264107 title "P1-365: A COMPARISON OF IN VIVO POTENCY IN TWO BACE INHIBITORS AS DETERMINED IN HUMANS AND DOGS" @default.
- W2082264107 doi "https://doi.org/10.1016/j.jalz.2014.05.607" @default.
- W2082264107 hasPublicationYear "2014" @default.
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