A phase I ascending single-dose study of the safety, tolerability, and pharmacokinetics of bosutinib (SKI-606) in healthy adult subjects
A phase I ascending single-dose study of the safety, tolerability, and pharmacokinetics of bosutinib (SKI-606) in healthy adult subjects
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DOI：
10.1007/s00280-011-1688-7
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发表时间：
2012-01-01
影响因子：
3
通讯作者：
Sonnichsen, Daryl
中科院分区：
文献类型：
--
作者：
Abbas, Richat;Hug, Bruce A.;Sonnichsen, Daryl
目的波苏替尼(SKI-606)是一种双重的Src/Abl酪氨酸激酶抑制剂，临床上用于治疗慢性粒细胞白血病(CML)。为支持临床研究，我们对博苏替尼在健康成人中的安全性、耐受性和药代动力学(PK)进行了剂量递增和食品效应评价。方法采用随机、双盲、安慰剂对照、单次递增剂量序贯分组研究。受试者随机接受博苏替尼200、400、600和800毫克的饮食治疗；200和400毫克的不饮食治疗；或安慰剂治疗。采用高效液相色谱-串联质谱法测定血药浓度。结果55名入选受试者中，33名(81%)受试者在接受博苏替尼治疗后发生不良事件(AEs)。常见的不良反应包括腹泻(39%)、恶心(29%)和头痛(22%)。博苏替尼200-600 mg配餐安全，耐受性好。波苏替尼的暴露剂量(C(Max)和AUC)在200-800 mg范围内与食物呈线性关系。吸收相对较慢；表观分布体积(V(Z)/F)为1 31~2 14 L/kg，平均表观清除(CL/F)为2.2 5~3.81 L/h/kg。食物效应初步评估显示，与禁食条件下相比，与禁食条件下相比，摄入波苏替尼的C(Max)增加了2.52倍(P=0.002)，AUC增加了2.28倍(P=0.002)；与食物同时服用400 mg博苏替尼可使AUC值增加约1.5倍(P=0.037)。约1%的剂量通过尿排出。结论博素替尼200~600 mg与食物配伍安全，耐受性好。在进食条件下，博苏替尼的暴露呈线性和剂量正比，C(Max)增加约1.5倍。T(1/2)支持每天给药一次。
Purpose Bosutinib (SKI-606), a dual Src/Abl tyrosine kinase inhibitor, is in clinical development for the treatment of patients with chronic myelogenous leukemia (CML). To support clinical development, we conducted a dose-escalation and food-effect evaluation of safety, tolerability, and pharmacokinetics (PK) of bosutinib in healthy adults.Methods This was a randomized, double-blind, placebo-controlled, single-ascending dose, sequential-group study of oral bosutinib. Subjects randomly received bosutinib 200, 400, 600, and 800 mg with food; 200 and 400 mg without food; or placebo. Plasma concentrations were determined by a liquid chromatography-tandem mass spectrometry assay. Non-compartmental PK analyses were performed, and power models assessed dose linearity.Results Of 55 enrolled subjects, 33 (81%) subjects had adverse events (AEs) after receiving bosutinib. Common AEs included diarrhea (39%), nausea (29%), and headache (22%). Bosutinib 200-600 mg with food was safe and well tolerated. Bosutinib exposures (C (max) and AUC) were linear and dose proportional from 200 to 800 mg with food. Absorption was relatively slow; median time to C (max) was 6 h. Apparent volume of distribution (V (z)/F) was 131-214 L/kg, mean apparent clearance (CL/F) was 2.25-3.81 L/h/kg, and mean terminal elimination half-life (t (1/2)) was 32-39 h. Preliminary food effect assessment showed that exposure to bosutinib increased by similar to 2.52-fold (P = 0.002) for C (max) and similar to 2.28-fold (P = 0.002) for AUC when 200 mg bosutinib was administered with food compared with administration under fasting conditions; administration of 400 mg bosutinib with food increased AUC by similar to 1.5-fold (P = 0.037). Approximately 1% of administered dose was excreted in urine.Conclusions Bosutinib 200-600 mg with food was safe and well tolerated. Under fed conditions, bosutinib exposures were linear and dose proportional, and C (max) increased by similar to 1.5-fold. The t (1/2) supported a once-daily dosing regimen.