In discovery programs for CNS targets, prediction of human brain penetration is critical for predicting efficacious exposure and dose. To predict brain penetration, compounds with favorable in vitro permeability and Pgp efflux parameters are typically evaluated in animal models (usually mouse) to determine the penetrance of unbound drug from the plasma into the CNS (Kpu,u). Variations between preclinical species, including mice, and humans in Pgp expression and measured Kpu,u have been observed, suggesting mouse may not always be a good surrogate for human when evaluating brain penetration. In a BACE inhibitor (Alzheimer’s disease treatment) development program, a CSF cannulated dog model was utilized to evaluate PD following administration of BACE1 inhibitors. Beagle dog was chosen because the sequences of BACE1 and its substrate, APP, are very similar in humans and dogs. The cannulation and subsequent weekly CSF collection was well tolerated, with cannula patency generally maintained for a minimum of 6 months. Full PK time courses of both plasma and CSF in individual animals were collected, allowing determination of CSF:plasma AUC ratios. These ratios, along with CSF biomarker data, were used for PKPD modeling and dose projections in humans. Four BACE1 inhibitors developed through this paradigm have been administered to humans. In addition, 2 externally developed BACE1 inhibitors with reported human CSF:plasma ratios were evaluated with the dog model. These six compounds span a range of CNS penetration, physical-chemical properties, and protein binding. CSF Kpu,u in humans was very well predicted from dog data, including compounds for which mouse underpredicted human Kpu,u. These data indicate dog is an excellent predictor of CNS penetration for the BACE1 inhibitor program. This model allowed non-terminal, serial CSF collections and required a relatively small number of animals to prosecute entire discovery programs. Assessment of applicability for other scaffolds is warranted.

Use of a CSF cannulated dog model in development of BACE1 inhibitors

2019 Fall National Meeting

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