Pharmacokinetics in Rat of P8, a Peptide Drug Candidate for the Treatment of Alzheimer's Disease: Stability and Delivery to the Brain.
Pharmacokinetics in Rat of P8, a Peptide Drug Candidate for the Treatment of Alzheimer's Disease: Stability and Delivery to the Brain.
复制标题
DOI：
10.3233/adr-180078
复制
发表时间：
2018-10-24
期刊：
影响因子：
--
通讯作者：
Johnson D
中科院分区：
文献类型：
--
作者：
Dewji NN;Azar MR;Hanson LR;Frey Ii WH;Morimoto BH;Johnson D
实现旨在降低淀粉样蛋白-β（Aβ）的作用的阿尔茨海默病（AD）的治疗的策略主要涉及抑制或修饰β-或γ-分泌酶的活性或通过使用单克隆抗体（MAb）。我们以前提供了一个新的，早期和有效的方法治疗AD的战略，不针对分泌酶的潜力。我们发现，含有DEEEDEEL序列的肽家族和另一个独立的肽（均来自PS-1的氨基末端）均能够显著降低体外和mThy 1-hAPP转基因小鼠中Aβ的产生。这些多肽与淀粉样β蛋白前体（AβPP）的胞外域有较强的特异性结合，不影响β或γ分泌酶的催化活性，也不影响AβPP的水平。开发任何AD治疗药物的关键是要求其稳定并可递送至大脑。我们在此报告了我们的主要候选物P8通过静脉内（IV）、鼻内（IN）和皮下（SC）给药的代谢稳定性和向大鼠脑递送的数据。P8单次给药后P8在大鼠血浆和CSF中的药代动力学（PK）表明，SC给药比IN给药吸收更好，是进一步开发P8作为临床候选药物的首选给药方法。
Strategies to achieve a therapy for Alzheimer’s disease (AD) aimed at reducing the effects of amyloid-β (Aβ) have largely involved inhibiting or modifying the activities of the β- or γ-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 Aβ in vitro and in mThy1-hAPP transgenic mice. These peptides gave a strong and specific binding with the ectodomain of amyloid-β protein precursor (AβPP) and did not affect the catalytic activities of β- or γ-secretase, or the level of AβPP. 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.