Clinical Pharmacology, Hoffman-La Roche, Nutley, New Jersey 07110, USA.
Clin Cancer Res. 2009 Dec 1;15(23):7368-74. doi: 10.1158/1078-0432.CCR-09-1696. Epub 2009 Nov 24.
CH4987655 (RO4987655) is an orally active and highly selective small-molecule MEK inhibitor. It potently inhibits mitogen-activated protein kinase signaling pathway activation and tumor cell growth, with an in vitro IC(50) of 5.2 nmol/L for inhibition of MEK1/2. Single-agent oral administration of CH4987655 resulted in complete tumor regressions in xenograft models.
All 40 subjects received a single oral dose followed by 72 hrs of pharmacokinetic, pharmacodynamic, and safety/tolerability assessments. The pharmacodynamics were measured by changes in phosphorylated extracellular signal-regulated kinase (pERK) levels in a surrogate tissue peripheral blood mononuclear cells ex vivo stimulated by PMA.
Doses of 0.5, 1, 2, 3, and 4 mg were safe and well tolerated. No clinically significant safety event was observed. A total of 26 adverse events (n = 15) were reported: 21 mild, 5 moderate, and none severe. Moderate adverse events were experienced by one subject at 1 mg (autonomic nervous system imbalance) and three subjects at 4 mg (diarrhea, abdominal pain, autonomic nervous system and acne). CH4987655 was rapidly absorbed with a t(max) of approximately 1 h. Exposures were dose proportional from 0.5 to 4 mg. The disposition was biphasic with a terminal t(1/2) of approximately 25 hr. Intersubject variability was low, 9% to 23% for C(max) and 14% to 25% for area-under-the-curve (AUC). pERK inhibition was exposure dependent and was greater than 80% inhibition at higher doses. The pharmacokinetic-pharmacodynamic relationship was characterized by an inhibitory E(max) model (E(max) approximately 100%; IC(50) 40.6 ng/mL) using nonlinear mixed-effect modeling.
A significant extent of pERK inhibition was achieved for a single dose that was considered to be safe and well tolerated in healthy volunteers.
CH4987655（RO4987655）是一种口服活性且高度选择性的小分子 MEK 抑制剂。它能够有效抑制丝裂原活化蛋白激酶信号通路的激活和肿瘤细胞的生长，在体外对 MEK1/2 的抑制 IC50 为 5.2nmol/L。在异种移植模型中，单一口服给予 CH4987655 可导致完全肿瘤消退。
所有 40 名受试者接受单次口服给药，随后进行 72 小时的药代动力学、药效学和安全性/耐受性评估。药效学通过 PMA 体外刺激外周血单个核细胞（pERK）的磷酸化水平变化来测量。
0.5、1、2、3 和 4mg 的剂量安全且耐受良好。未观察到临床意义上的安全性事件。共报告了 26 起不良事件（n=15）：21 起轻度，5 起中度，无重度。1 名受试者在 1mg 时（自主神经系统失衡）和 3 名受试者在 4mg 时（腹泻、腹痛、自主神经系统和痤疮）出现中度不良事件。CH4987655 吸收迅速，t(max)约为 1 小时。0.5 至 4mg 剂量暴露呈剂量比例关系。处置呈双相，终末 t1/2 约为 25 小时。个体间变异性低，C(max)的 9%至 23%和 AUC 的 14%至 25%。pERK 抑制与暴露量相关，高剂量时抑制率大于 80%。药代动力学-药效学关系通过非线性混合效应模型，以抑制 E(max)模型（E(max)约为 100%；IC50 为 40.6ng/mL）进行特征描述。
在健康志愿者中，单次给予可达到显著程度的 pERK 抑制，且被认为安全耐受。
