Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Groton, CT 06340, USA. Yasong.Lu @ pfizer.com
Neurodegener Dis. 2013;12(1):36-50. doi: 10.1159/000341217. Epub 2012 Aug 21.
Reducing brain β-amyloid (Aβ) via inhibition of β-secretase, or inhibition/modulation of γ-secretase, has been widely pursued as a potential disease-modifying treatment for Alzheimer's disease. Compounds that act through these mechanisms have been screened and characterized with Aβ lowering in the brain and/or cerebrospinal fluid (CSF) as the primary pharmacological end point. Interpretation and translation of the pharmacokinetic (PK)/pharmacodynamic (PD) relationship for these compounds is complicated by the relatively slow Aβ turnover process in these compartments.
To understand Aβ turnover kinetics in preclinical species and humans.
We collected CSF Aβ dynamic data after β- or γ-secretase inhibitor treatment from in-house experiments and the public domain, and analyzed the data using PK/PD modeling to obtain CSF Aβ turnover rates (kout) in the mouse, dog, monkey and human.
The kout for CSF Aβ40 follows allometry (kout = 0.395 × body weight(-0.351)). The kout for CSF Aβ40 is approximately 2-fold higher than the turnover of CSF in rodents, but in higher species, the two are comparable.
The turnover of CSF Aβ40 was systematically examined, for the first time, in multiple species through quantitative modeling of multiple data sets. Our result suggests that the clearance mechanisms for CSF Aβ in rodents may be different from those in the higher species. The understanding of Aβ turnover has considerable implications for the discovery and development of Aβ-lowering therapeutics, as illustrated from the perspectives of preclinical PK/PD characterization and preclinical-to-clinical translation.
通过抑制β-分泌酶或γ-分泌酶的抑制/调节来减少脑β-淀粉样蛋白（Aβ）已被广泛研究作为治疗阿尔茨海默病的潜在疾病修饰治疗方法。通过这些机制起作用的化合物已被筛选和表征，其特征在于大脑和/或脑脊液（CSF）中的 Aβ 降低作为主要的药理学终点。由于这些隔室中 Aβ 的周转率相对较慢，因此这些化合物的药代动力学（PK）/药效动力学（PD）关系的解释和翻译变得复杂。
了解临床前物种和人类中 Aβ 的周转动力学。
我们从内部实验和公共领域收集了β-或γ-分泌酶抑制剂治疗后 CSF Aβ 的动态数据，并使用 PK/PD 建模分析数据，以获得小鼠、狗、猴子和人类 CSF Aβ40 的周转率（kout）。
CSF Aβ40 的 kout 遵循异速生长（kout = 0.395 × 体重(-0.351)）。CSF Aβ40 的 kout 大约是啮齿动物中 CSF 周转率的 2 倍，但在较高的物种中，两者相当。
通过对多个数据集的定量建模，首次在多个物种中系统地检查了 CSF Aβ40 的周转。我们的结果表明，啮齿动物 CSF Aβ 的清除机制可能与较高物种不同。对 Aβ 周转的理解对 Aβ 降低治疗药物的发现和开发具有重要意义，从临床前 PK/PD 特征和临床前到临床的转化角度说明了这一点。
