Pharmacokinetics in rat of P8, a peptide drug candidate for the treatment of Alzheimer's disease: stability and delivery to the brain
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Strategies to achieve a therapy for Alzheimer's disease (AD) aimed at reducing the effects of amyloid-beta (Abeta) have largely involved inhibiting or modifying the activities of the beta- or gamma-secretases or by the use of monoclonal antibodies (MAb). We previously offered the potential for a new, early and effective approach for the treatment of AD by a strategy that does not target the secretases. We showed that a family of peptides containing the DEEEDEEL sequence and another independent peptide, all derived from the amino terminus of PS-1, are each capable of markedly reducing the production of Abeta in vitro and in mThy1-hAPP transgenic mice. These peptides gave a strong and specific binding with the ectodomain of amyloid-beta protein precursor (AbetaPP) and did not affect the catalytic activities of beta- or gamma-secretase, or the level of AbetaPP. Critical to the development of any therapeutic for AD is the requirement that it is stable and can be delivered to the brain. We report here data on the metabolic stability and delivery to the rat brain of our lead candidate P8 by intravenous (IV), intranasal (IN), and subcutaneous (SC) administration. Pharmacokinetics (PK) of P8 in rat plasma and CSF following a single dose of P8 demonstrate that SC administration gives better absorption compared to IN and is the delivery method of choice for the further development of P8 as a clinical candidate.
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