A phase I, open-label, randomized crossover study to assess the effect of dosing of the MEK 1/2 inhibitor Selumetinib (AZD6244; ARRY-142866) in the presence and absence of food in patients with advanced solid tumors.
A phase I, open-label, randomized crossover study to assess the effect of dosing of the MEK 1/2 inhibitor Selumetinib (AZD6244; ARRY-142866) in the presence and absence of food in patients with advanced solid tumors.
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DOI：
10.1007/s00280-011-1732-7
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发表时间：
2011-12
影响因子：
3
通讯作者：
Middleton, Mark
中科院分区：
文献类型：
--
作者：
Leijen, Suzanne;Soetekouw, Patricia M. M. B.;Evans, T. R. Jeffry;Nicolson, Marianne;Schellens, Jan H. M.;Learoyd, Maria;Grinsted, Lynda;Zazulina, Victoria;Pwint, Thinn;Middleton, Mark
这项I期研究评估了食物是否影响晚期实体恶性肿瘤患者的司美替尼吸收速率和程度，并确定了进食和空腹状态下司美替尼及其活性代谢产物N-去甲基-司美替尼的安全性、耐受性和药代动力学（PK）特征。第1天单次75 mg司美替尼随餐服用，然后在第8天空腹至少10 h后单次75 mg司美替尼给药，反之亦然，然后从第10天开始每日两次75 mg司美替尼给药。在第1天和第8天测定血浆浓度和PK参数。患者可以继续接受selumetinib，只要他们从治疗中获益。共有31例患者随机接受司美替尼治疗; 15例患者接受进食/空腹序列治疗，16例患者接受空腹/进食序列治疗。分别对11例和10例患者进行了全面PK采样。与空腹状态相比，餐后状态下司美替尼的Cmax和AUC的几何最小二乘均值分别降低62%（比值0.38 90% CI 0.29，0.50）和19%（比值0.81 90% CI 0.74，0.88）。司美替尼（进食）的吸收速率（tmax）延迟约2.5小时（中位数）。还观察到活性代谢产物N-去甲基-司美替尼的食物效应。司美替尼耐受性良好。食物的存在降低了司美替尼的吸收程度。对于进一步的临床研究，建议空腹服用司美替尼。司美替尼在晚期癌症人群中显示出可接受的安全性特征。
This Phase I study assessed whether food influences the rate and extent of selumetinib absorption in patients with advanced solid malignancies and determined the safety, tolerability, and pharmacokinetic (PK) profile of selumetinib and its active metabolite N-desmethyl-selumetinib in fed and fasted states. A single dose of 75 mg selumetinib was to be taken with food on Day 1 followed by a single dose of 75 mg after fasting for at least 10 h on Day 8, or vice versa, followed by twice daily dosing of 75 mg selumetinib from Day 10. Plasma concentrations and PK parameters were determined on Days 1 and 8. Patients could continue to receive selumetinib for as long as they benefitted from treatment. In total, 31 patients were randomized to receive selumetinib; 15 to fed/fasted sequence and 16 to fasted/fed sequence. Comprehensive PK sampling was performed on 11 and 10 patients, respectively. The geometric least-squares means of Cmax and AUC for selumetinib were reduced by 62% (ratio 0.38 90% CI 0.29, 0.50) and 19% (ratio 0.81 90% CI 0.74, 0.88), respectively, under fed compared with fasting conditions. The rate of absorption (tmax) of selumetinib (fed) was delayed by approximately 2.5 h (median). The food effect was also observed for the active metabolite N-desmethyl-selumetinib. Selumetinib was well tolerated. The presence of food decreased the extent of absorption of selumetinib. It is recommended that for further clinical studies, selumetinib be taken on an empty stomach. Selumetinib demonstrated an acceptable safety profile in the advanced cancer population.
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影响因子：
5.7
作者：
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通讯作者：
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影响因子：
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