A phase I and pharmacokinetic study of sunitinib administered daily for 2 weeks, followed by a 1-week off period
A phase I and pharmacokinetic study of sunitinib administered daily for 2 weeks, followed by a 1-week off period
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DOI：
10.1007/s00280-007-0498-4
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发表时间：
2008-03-01
影响因子：
3
通讯作者：
Slamon, Dennis
中科院分区：
文献类型：
--
作者：
Britten, Carolyn D.;Kabbinavar, Fairooz;Slamon, Dennis
舒尼替尼是一种口服多靶点酪氨酸激酶抑制剂，可抑制VEGFR、PDGFR、FLT 3、KIT和RET，目前已获批用于治疗伊马替尼难治性GIST和晚期肾细胞癌，剂量为50 mg/d，持续4周，随后停药2周（4/2方案）。本试验进行调查的安全性，耐受性和药代动力学舒尼替尼50毫克，每天2周，随后1周的关闭期（2/1 schedule）。实验设计12例晚期难治性恶性肿瘤患者用舒尼替尼治疗的2/1时间表。强化安全性监测包括连续测量左心室射血分数（LVEF）。广泛的药代动力学采样进行第1和第14天的课程1，并在第14天的课程2和3.Results舒尼替尼和SU 12662代谢物进行评估共12例患者接受了50个疗程的平均（+/- SD）停药期为11.5 +/- 5.7天。2例患者发生DLT：在疗程1中，1例患者出现无症状的4级脂肪酶和淀粉酶升高，另1例患者出现无症状的2级LVEF下降。总共有5名患者表现出无症状的2级左心室射血分数下降。其他主要影响与舒尼替尼既往经验相似，包括疲劳、骨髓抑制、皮肤变色和胃肠道影响。药代动力学研究显示舒尼替尼或SU 12662无显著蓄积。1例甲状腺乳头状癌患者部分缓解，并在研究16个疗程，随后由一个额外的18个疗程的延续protocol.Conclusion舒尼替尼50 mg的2/1时间表是可以耐受的，并没有显着的药物蓄积被证明。该给药方案的安全性特征与舒尼替尼按照给药4周、停药2周的给药方案给药时的安全性特征一致。
Purpose Sunitinib, an oral multitargeted tyrosine kinase inhibitor that inhibits VEGFR, PDGFR, FLT3, KIT, and RET, is currently approved for the treatment of imatinib-refractory GIST and advanced renal cell carcinoma at a dose of 50 mg daily for 4 weeks followed by a 2-week off period (4/2 schedule). This trial was performed to investigate the safety, tolerability, and pharmacokinetics of sunitinib 50 mg daily for 2 weeks followed by a 1-week off period (2/1 schedule).Experimental design Twelve patients with advanced refractory malignancies were treated with sunitinib on the 2/1 schedule. Intensive safety monitoring included serial measurements of left ventricular ejection fraction (LVEF). Extensive pharmacokinetic sampling was performed on days 1 and 14 of course 1, and on day 14 of courses 2 and 3 to evaluate sunitinib and the SU12662 metabolite.Results Twelve patients received a total of 50 courses with an average (+/- SD) off-drug period of 11.5 +/- 5.7 days. Two patients experienced DLT: one patient had asymptomatic grade 4 elevations in lipase and amylase, and another patient had an asymptomatic grade 2 decline in LVEF in course 1. In total, five patients demonstrated asymptomatic grade 2 declines in LVEF. Other principal effects were similar to previous experience with sunitinib, including fatigue, myelosuppression, skin discoloration, and gastrointestinal effects. Pharmacokinetic studies revealed no significant accumulation of sunitinib or SU12662. One patient with papillary thyroid cancer developed a partial response, and was on study for 16 courses, followed by an additional 18 courses on a continuation protocol.Conclusion The 2/1 schedule of sunitinib 50 mg was tolerable, and no significant drug accumulation was demonstrated. The safety profile on this schedule was consistent with the safety profile of sunitinib when administered on a 4-week on, 2-week off schedule.