Pfizer Inc, Cambridge, Massachusetts, USA.
Sunovion Pharmaceuticals, Marlborough, Massachusetts, USA.
Clin Pharmacol Ther. 2020 Jan;107(1):211-220. doi: 10.1002/cpt.1570. Epub 2019 Sep 11.
γ-Secretase modulators (GSMs) represent a promising therapy for Alzheimer's disease by reducing pathogenic amyloid-β (Aβ) peptide production. Three phase I studies (NCT02316756, NCT02407353, and NCT02440100) investigated the safety/tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the oral GSM, PF-06648671. A PK/PD indirect-response model was developed (using biomarker data) to simultaneously characterize differential effects of PF-06648671 on multiple Aβ species in cerebrospinal fluid (CSF). Healthy subjects (n = 120) received single doses or multiple-ascending doses of PF-06648671/placebo for 14 days. No serious adverse events occurred; severe adverse eventswere deemed not drug related. PF-06648671 decreased Aβ42 and Aβ40 concentrations in CSF, with greater effects on Aβ42, and increased Aβ37 and Aβ38 levels, particularly Aβ37. No significant change in total Aβ was observed. The PK/PD model well described the tendency of observed CSF Aβ data and the steady-state effects of PF-06648671, supporting its use for predicting central Aβ effects and optimal dose selection for GSMs in future trials.
γ-分泌酶调节剂（GSMs）通过减少致病淀粉样蛋白-β（Aβ）肽的产生，为阿尔茨海默病提供了一种很有前途的治疗方法。三项 I 期研究（NCT02316756、NCT02407353 和 NCT02440100）考察了口服 GSM PF-06648671 的安全性/耐受性、药代动力学（PKs）和药效动力学（PDs）。建立了一个 PK/PD 间接反应模型（使用生物标志物数据），以同时描述 PF-06648671 对脑脊液（CSF）中多种 Aβ 物种的差异作用。120 名健康受试者接受了单次或多次递增剂量的 PF-06648671/安慰剂，为期 14 天。未发生严重不良事件；严重不良事件被认为与药物无关。PF-06648671 降低了 CSF 中的 Aβ42 和 Aβ40 浓度，对 Aβ42 的作用更大，并增加了 Aβ37 和 Aβ38 的水平，尤其是 Aβ37。总 Aβ 无明显变化。PK/PD 模型很好地描述了 CSF Aβ 数据的趋势和 PF-06648671 的稳态效应，支持其用于预测中枢 Aβ 效应和未来试验中 GSM 的最佳剂量选择。
