Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium.
J Clin Pharmacol. 2011 Dec;51(12):1674-84. doi: 10.1177/0091270010386226. Epub 2011 Jan 5.
Sorafenib (twice daily [bid]) plus capecitabine (2 weeks on schedule/1 week off schedule) safety and pharmacokinetics were investigated in patients with advanced solid tumors (N = 35). Cohort 1 (n = 13) included sorafenib 200 mg bid and capecitabine 1050 mg/m(2) bid; cohort 2 (n = 4), sorafenib 400 mg bid and capecitabine 1050 mg/m(2) bid; cohort 3 (n = 6), sorafenib 200 mg bid and capecitabine 1050 mg/m(2) bid (cycles 1 and 2), then 400 mg bid and capecitabine 1050 mg/m(2) bid (cycle 3 onwards); and cohort 4 (n = 12), sorafenib 400 mg bid and capecitabine 850 mg/m(2) bid. The combination of sorafenib and capecitabine was generally well tolerated. Most frequent drug-related adverse events were hand-foot skin reaction (HFSR, 89%), diarrhea (71%), and fatigue (69%). The HFSR was dose-limiting toxicities in 6 patients. Sorafenib exposure (C(max) and AUC(0-12)) was unaffected by concomitant capecitabine. Concomitant sorafenib moderately increased capecitabine and 5-fluorouracil (metabolite) exposure when the capecitabine dose was 1050 mg/m(2) bid. Simultaneous administration of 400 mg bid sorafenib and 850 mg/m(2) bid capecitabine, however, had only minor effects on the exposure to capecitabine and 5-fluorouracil. Based on the overall toxicity profile and pharmacokinetic parameters, the recommended phase 2 doses were therefore sorafenib 400 mg bid and capecitabine 850 mg/m(2) bid, as scheduled above.
索拉非尼（bid）加卡培他滨（schedule/1 周停药）治疗晚期实体瘤患者的安全性和药代动力学（n=35）。第 1 队列（n=13）包括索拉非尼 200mg bid 和卡培他滨 1050mg/m(2)bid；第 2 队列（n=4），索拉非尼 400mg bid 和卡培他滨 1050mg/m(2)bid；第 3 队列（n=6），索拉非尼 200mg bid 和卡培他滨 1050mg/m(2)bid（第 1 和第 2 周期），然后 400mg bid 和卡培他滨 1050mg/m(2)bid（第 3 周期及以后）；第 4 队列（n=12），索拉非尼 400mg bid 和卡培他滨 850mg/m(2)bid。索拉非尼和卡培他滨联合治疗通常耐受性良好。最常见的药物相关不良事件为手足皮肤反应（HFSR，89%）、腹泻（71%）和疲劳（69%）。6 例患者出现剂量限制毒性的 HFSR。卡培他滨不影响索拉非尼的暴露（C(max)和 AUC(0-12)）。当卡培他滨剂量为 1050mg/m(2)bid 时，同时使用索拉非尼可使卡培他滨和 5-氟尿嘧啶（代谢物）的暴露适度增加。然而，同时给予 400mg bid 索拉非尼和 850mg/m(2)bid 卡培他滨对卡培他滨和 5-氟尿嘧啶的暴露仅有轻微影响。基于总体毒性特征和药代动力学参数，因此推荐的 2 期剂量为索拉非尼 400mg bid 和卡培他滨 850mg/m(2)bid，按上述方案进行。
