Division of Cancer Medicine, Department of Investigational Cancer Therapeutics, Unit 455, University of Texas MD Anderson Cancer Center, Houston, TX 77030-1402, USA.
Invest New Drugs. 2012 Feb;30(1):327-34. doi: 10.1007/s10637-010-9536-x. Epub 2010 Sep 15.
This phase I, open-label, randomized, 2-part crossover study assessed the safety, pharmacokinetics and relative bioavailability of single doses of the anticancer MET inhibitor foretinib (formerly known as GSK1363089, EXEL-2880 and XL-880) free base tablet formulation compared to a bisphosphate salt capsule formulation (Part 1), and assessed the safety, efficacy, and pharmacokinetics of the bisphosphate salt capsule administered 3 times a week in cancer patients (Part 2).
In Part 1, patients were randomized in a crossover manner to receive a single oral dose of foretinib formulated as a bisphosphate salt capsule (240 mg; 183 mg free base equivalent) followed one week later by a single dose of a free base tablet (180 mg), or vice versa where the treatment sequence was reversed. In Part 2, patients self-administered oral doses of bisphosphate salt capsules (200 mg) 3 times a week until disease progression.
Twelve patients with solid tumors were enrolled and completed Part 1, and 10 patients continued into Part 2. Most AEs were mild or moderate in severity. The most common drug-related AEs were fatigue, diarrhea, and nausea. The least-squares (LS) mean total area under the curve was 3144 and 3514 ng*h/mL for the free base tablet and bisphosphate salt capsule, respectively, with a ratio of 0.89 (90% confidence interval, CI: 0.69, 1.16). The LS mean maximal concentration (Cmax) was 81.6 and 98.5 ng/mL for the free base and bisphosphate salt, respectively, with a ratio of 0.83 (90% confidence interval, CI: 0.67, 1.02). The time to reach Cmax was ∼4 h for both formulations. The pharmacokinetics of foretinib were not clinically different between the 2 formulations. Of the 10 patients assessed for efficacy, 3 patients achieved stable disease.
Foretinib was well tolerated as single doses of both the free base and bisphosphate salt formulations. The pharmacokinetics and relative bioavailability of the 2 formulations were not clinically different. The bisphosphate salt formulation was well tolerated on a 3-times a week dosing schedule, and reached steady-state plasma concentration after 2 weeks.
本 I 期、开放标签、随机、2 部分交叉研究评估了单剂量抗癌 MET 抑制剂 foretinib（以前称为 GSK1363089、EXEL-2880 和 XL-880）游离碱片剂与双膦酸盐盐胶囊制剂（第 1 部分）的安全性、药代动力学和相对生物利用度，并评估了每周 3 次给予双膦酸盐盐胶囊的安全性、疗效和药代动力学在癌症患者中（第 2 部分）。
在第 1 部分中，患者以交叉方式随机接受单剂量口服 foretinib 双膦酸盐盐胶囊（240mg；183mg 游离碱当量），一周后再给予单剂量游离碱片剂（180mg），或反之亦然，其中治疗顺序相反。在第 2 部分中，患者自行口服双膦酸盐盐胶囊（200mg），每周 3 次，直至疾病进展。
12 名实体瘤患者入组并完成了第 1 部分，其中 10 名患者继续进入第 2 部分。大多数不良事件的严重程度为轻度或中度。最常见的药物相关不良事件是疲劳、腹泻和恶心。游离碱片剂和双膦酸盐盐胶囊的最小二乘（LS）均值总曲线下面积分别为 3144 和 3514ng*h/mL，比值为 0.89（90%置信区间，CI：0.69，1.16）。游离碱和双膦酸盐盐的 LS 均值最大浓度（Cmax）分别为 81.6 和 98.5ng/mL，比值为 0.83（90%置信区间，CI：0.67，1.02）。两种制剂的 Cmax 达到时间约为 4 小时。两种制剂的 foretinib 药代动力学无临床差异。在评估疗效的 10 名患者中，3 名患者病情稳定。
游离碱和双膦酸盐盐两种制剂的单剂量均耐受良好。两种制剂的药代动力学和相对生物利用度无临床差异。双膦酸盐盐制剂每周 3 次给药耐受性良好，给药 2 周后达到稳定的血浆浓度。
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