MS#220-4546, Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA.
J Pharmacol Exp Ther. 2012 Aug;342(2):366-75. doi: 10.1124/jpet.112.192625. Epub 2012 May 4.
Reducing the generation of amyloid-β (Aβ) in the brain via inhibition of β-secretase or inhibition/modulation of γ-secretase has been pursued as a potential disease-modifying treatment for Alzheimer's disease. For the discovery and development of β-secretase inhibitors (BACEi), γ-secretase inhibitors (GSI), and γ-secretase modulators (GSM), Aβ in cerebrospinal fluid (CSF) has been presumed to be an effect biomarker for Aβ lowering in the brain. However, this presumption is challenged by the lack of quantitative understanding of the relationship between brain and CSF Aβ lowering. In this study, we strived to elucidate how the intrinsic pharmacokinetic (PK)/pharmacodynamic (PD) relationship for CSF Aβ lowering is related to that for brain Aβ through quantitative modeling of preclinical data for numerous BACEi, GSI, and GSM across multiple species. Our results indicate that the intrinsic PK/PD relationship in CSF is predictive of that in brain, at least in the postulated pharmacologically relevant range, with excellent consistency across mechanisms and species. As such, the validity of CSF Aβ as an effect biomarker for brain Aβ lowering is confirmed preclinically. Meanwhile, we have been able to reproduce the dose-dependent separation between brain and CSF effect profiles using simulations. We further discuss the implications of our findings to drug discovery and development with regard to preclinical PK/PD characterization and clinical prediction of Aβ lowering in the brain.
通过抑制β-分泌酶或抑制/调节γ-分泌酶来减少大脑中淀粉样蛋白-β（Aβ）的产生，一直被视为治疗阿尔茨海默病的潜在疾病修饰治疗方法。对于β-分泌酶抑制剂（BACEi）、γ-分泌酶抑制剂（GSI）和 γ-分泌酶调节剂（GSM）的发现和开发，脑脊液（CSF）中的 Aβ 被假定为大脑中 Aβ 降低的效应生物标志物。然而，由于缺乏对大脑和 CSF Aβ 降低之间关系的定量理解，这种假设受到了挑战。在这项研究中，我们通过对多种 BACEi、GSI 和 GSM 在多个物种中的临床前数据进行定量建模，努力阐明 CSF 中 Aβ 降低的内在药代动力学（PK）/药效动力学（PD）关系与大脑 Aβ 降低的内在 PK/PD 关系之间的关系。我们的结果表明，CSF 中的内在 PK/PD 关系至少在假定的药理相关范围内可预测大脑中的关系，不同机制和物种之间具有极好的一致性。因此，CSF Aβ 作为大脑 Aβ 降低的效应生物标志物的有效性在临床前得到了证实。同时，我们能够使用模拟重现大脑和 CSF 效应曲线之间的剂量依赖性分离。我们进一步讨论了我们的发现对药物发现和开发的影响，涉及临床前 PK/PD 特征描述和大脑中 Aβ 降低的临床预测。
