Hidalgo Manuel, Bloedow Duane
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans St, Room 1M88, Baltimore, MD 21231, USA.
Semin Oncol. 2003 Jun;30(3 Suppl 7):25-33.
Pharmacokinetic and pharmacodynamic studies have an important role in the optimization of targeted agents. Phase I pharmacokinetic studies show that treatment with erlotinib HCl (Tarceva; Genentech Inc, South San Francisco, CA), an orally available epidermal growth factor receptor (HER1/EGFR)-tyrosine kinase inhibitor, on a daily, uninterrupted schedule is feasible. Also, plasma drug concentrations, likely to be clinically effective based on preclinical studies, are consistently achieved at the recommended phase II dose of 150 mg/day, the maximum tolerated dose. Pharmacodynamic studies are in progress to assess the activation of HER1/EGFR and associated downstream signaling pathways in tissue samples from patients treated with erlotinib. Expression of p27 is identified as a potential surrogate marker of erlotinib activity, and is a focus of ongoing and future studies. Also, studies indicate that skin may be a useful surrogate tissue for evaluating the pharmacodynamic effects of therapy. These studies will hopefully enable us to accurately assess the extent of target inhibition in patients treated with erlotinib and help optimize its clinical use.
药代动力学和药效学研究在优化靶向药物方面发挥着重要作用。I期药代动力学研究表明，盐酸厄洛替尼（特罗凯；基因泰克公司，加利福尼亚州南旧金山）是一种口服可用的表皮生长因子受体（HER1/EGFR）-酪氨酸激酶抑制剂，每日不间断给药方案是可行的。此外，根据临床前研究，在推荐的II期剂量150mg/天（即最大耐受剂量）下，始终能达到可能具有临床疗效的血浆药物浓度。目前正在进行药效学研究，以评估接受厄洛替尼治疗的患者组织样本中HER1/EGFR的激活及相关下游信号通路。p27的表达被确定为厄洛替尼活性的潜在替代标志物，是正在进行和未来研究的重点。此外，研究表明皮肤可能是评估治疗药效学效应的有用替代组织。这些研究有望使我们准确评估接受厄洛替尼治疗患者的靶点抑制程度，并有助于优化其临床应用。
