Strumberg D, Schultheis B, Adamietz I A, Christensen O, Buechert M, Kraetzschmar J, Rajagopalan P, Ludwig M, Frost A, Steinbild S, Scheulen M E, Mross K
Department of Haematology and Medical Oncology, University of Bochum (Marien Hospital, Herne), Herne, Germany.
Br J Cancer. 2008 Nov 18;99(10):1579-85. doi: 10.1038/sj.bjc.6604724.
Telatinib (BAY 57-9352) is an orally available, small-molecule inhibitor of vascular endothelial growth factor receptors 2 and 3 (VEGFR-2/-3) and platelet-derived growth factor receptor beta tyrosine kinases. In this multicentre phase I dose escalation study, 71 patients with refractory solid tumours were enroled into 14 days on/7 days off (noncontinuous dosing) or continuous dosing groups to receive telatinib two times daily (BID). Hypertension (23%) and diarrhoea (7%) were the most frequent study drug-related adverse events of CTC grade 3. The maximum-tolerated dose was not reached up to a dose of 1500 mg BID continuous dosing. Telatinib was rapidly absorbed with median t(max) of 3 hours or less. Geometric mean C(max) and AUC(0-12) increased in a less than dose-proportional manner and plateaued in the 900-1500 mg BID dose range. Two renal cell carcinoma patients reached a partial response. Tumour blood flow measured by contrast-enhanced magnetic resonance imaging and sVEGFR-2 plasma levels decreased with increasing AUC(0-12) of telatinib. Telatinib is safe and well tolerated up to a dose of 1500 mg BID continuous dosing. Based on pharmacokinetic and pharmacodynamic criteria, 900 mg telatinib BID continuously administered was selected as the recommended phase II dose.
替拉替尼（BAY 57-9352）是一种口服可用的小分子血管内皮生长因子受体2和3（VEGFR-2/-3）以及血小板衍生生长因子受体β酪氨酸激酶抑制剂。在这项多中心I期剂量递增研究中，71例难治性实体瘤患者被纳入14天服药/7天停药（非连续给药）或连续给药组，每日两次（BID）接受替拉替尼治疗。高血压（23%）和腹泻（7%）是最常见的3级与研究药物相关的不良事件。连续给药剂量达1500 mg BID时未达到最大耐受剂量。替拉替尼吸收迅速，中位达峰时间（t(max)）为3小时或更短。几何平均血药峰浓度（C(max)）和药时曲线下面积（AUC(0-12)）以小于剂量比例的方式增加，并在900-1500 mg BID剂量范围内达到平台期。两名肾细胞癌患者达到部分缓解。通过对比增强磁共振成像测量的肿瘤血流和可溶性血管内皮生长因子受体-2（sVEGFR-2）血浆水平随替拉替尼AUC(0-12)的增加而降低。连续给药剂量达1500 mg BID时，替拉替尼安全且耐受性良好。基于药代动力学和药效学标准，选择900 mg替拉替尼每日两次连续给药作为推荐的II期剂量。
