AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
Clin Ther. 2012 Jan;34(1):221-37. doi: 10.1016/j.clinthera.2011.11.011. Epub 2011 Dec 28.
Vandetanib is an orally available inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor and is rearranged during transfection tyrosine kinase activity. Development has included studies in non-small cell lung cancer and other tumor types. Accurate elimination kinetics were not determined in patient studies, and so the current human volunteer studies were performed to derive detailed kinetic data.
The aim of this study was to investigate pharmacokinetics, metabolism, excretion, and elimination kinetics after single oral doses of vandetanib in healthy subjects.
Three studies were conducted. In Study A (n = 23), cohorts of 8 subjects were randomized to receive double-blind, ascending doses of vandetanib (300-1200 mg) or placebo (6:2). Study B had a crossover design; subjects (n = 16) received vandetanib 300 mg under fed and fasted conditions. In Study C, subjects (n = 4) received [(14)C] vandetanib 800 mg. Blood samples were collected for pharmacokinetic analysis for up to 28 days after the dose (Studies A and B) and 42 days after the dose (Study C). Plasma (all studies) and urine (Study A only) samples were collected for determination of vandetanib concentrations. In Study C radioactivity was measured in plasma, blood, urine, and feces, and metabolites were identified chromatographically. Tolerability was evaluated by recording of adverse events, clinical chemistry, hematology and urinalysis parameters, vital signs, and ECGs (all studies).
Study A: mean (SD) age 34.4 (6.9) years; 23/23 male; mean (SD; range) weight 80.6 (8.1; 62-97) kg. Study B: mean (SD) age 35.3 (8.4) years; 15/16 male; mean (SD; range) weight 80.7 (11.2; 57-100) kg. Study C: mean (SD) age 60.3 (7.4) years; 4/4 male; mean (SD; range) weight 78.0 (7.7l; 72-87) kg. Pharmacokinetic parameters were consistent across all studies (Studies A and C, vandetanib 800 mg: geometric mean CL/F, 13.1-13.3 L/h; geometric mean apparent volume of distribution at steady state [V(SS)/F], 3592-4103 L; mean t(½), 215.8-246.6 hours). Vandetanib was absorbed and eliminated slowly after single oral doses. AUC(0-∞) and C(max) were not significantly affected by ingestion of food. Median (range) T(max) was 8 (3-18) hours after food and 6 (5-18) hours after fasting. In plasma, concentrations of total radioactivity were higher than vandetanib concentrations at all time points, indicating the presence of circulating metabolites. Unchanged vandetanib and 2 anticipated metabolites (N-desmethylvandetanib and vandetanib N-oxide) were detected in plasma, urine, and feces. A further trace minor metabolite (glucuronide conjugate) was found in urine and feces. Approximately two thirds of the dose was recovered in feces (44%) and urine (25%) over 21 days, underlining the importance of both routes of elimination. Adverse events were reported by all subjects in Study A apart from 2 at a vandetanib dose of 300 mg; 12/15 (80%) and 14/16 (88%) subjects who took vandetanib under fed and fasted conditions, respectively, in Study B; and 2/4 (50%) subjects in Study C. No serious adverse events were reported. Increasing doses of vandetanib, in Study A, were associated with variable increases in systolic and diastolic blood pressures and variable increases from baseline in QTc interval. Hematuria was reported by 3 subjects (vandetanib 300 mg) in Study A. Small but consistent increases from baseline in serum creatinine were noted in subjects who received vandetanib in these studies. No other clinically important changes were observed in clinical chemistry, hematology and urinalysis parameters, vital signs, and ECGs in any of the studies.
The pharmacokinetics of vandetanib after single oral doses to healthy subjects were defined and the metabolic pathway was proposed. Vandetanib was absorbed and eliminated slowly with a t(½) of ∼10 days after single oral doses. The extent of absorption was not significantly affected by the presence of food. Approximately two thirds of the dose was recovered in feces (44%) and urine (25%) over 21 days. Unchanged vandetanib and N-desmethyl and N-oxide metabolites were detected in plasma, urine, and feces. Vandetanib appeared to be was well tolerated in the populations studied.
凡德他尼是一种口服血管内皮生长因子受体 2 和表皮生长因子受体抑制剂，具有转染酪氨酸激酶活性。该药物已在非小细胞肺癌和其他肿瘤类型的研究中进行开发。在患者研究中未确定准确的消除动力学，因此进行了当前的人类志愿者研究以获得详细的动力学数据。
本研究旨在调查健康受试者单次口服凡德他尼后的药代动力学、代谢、排泄和消除动力学。
进行了三项研究。在研究 A（n=23）中，8 名受试者随机分为两组，分别接受双盲递增剂量的凡德他尼（300-1200mg）或安慰剂（6：2）。研究 B 采用交叉设计；16 名受试者在进食和禁食条件下接受凡德他尼 300mg。在研究 C 中，4 名受试者接受 [(14)C] 凡德他尼 800mg。在给药后 28 天（研究 A 和 B）和 42 天（研究 C）内采集血样进行药代动力学分析。在所有研究中采集血浆（所有研究）和尿液（仅研究 A）样本以测定凡德他尼浓度。在研究 C 中，在血浆、血液、尿液和粪便中测量放射性，并通过色谱法鉴定代谢物。通过记录不良事件、临床化学、血液学和尿液分析参数、生命体征和心电图（所有研究）评估耐受性。
研究 A：平均（SD）年龄 34.4（6.9）岁；23/23 名男性；平均（SD；范围）体重 80.6（8.1；62-97）kg。研究 B：平均（SD）年龄 35.3（8.4）岁；15/16 名男性；平均（SD；范围）体重 80.7（11.2；57-100）kg。研究 C：平均（SD）年龄 60.3（7.4）岁；4/4 名男性；平均（SD；范围）体重 78.0（7.7l；72-87）kg。药代动力学参数在所有研究中均一致（研究 A 和 C，凡德他尼 800mg：几何平均 CL/F，13.1-13.3L/h；几何平均稳态表观分布体积 [V（SS）/F]，3592-4103L；平均 t（½），215.8-246.6 小时）。单次口服后，凡德他尼吸收和消除缓慢。AUC（0-∞）和 C（max）不受食物摄入的影响。中位（范围）T（max）为进食后 8（3-18）小时，禁食后 6（5-18）小时。在血浆中，总放射性浓度在所有时间点均高于凡德他尼浓度，表明存在循环代谢物。在血浆、尿液和粪便中均检测到未改变的凡德他尼和 2 种预期代谢物（N-去甲基凡德他尼和凡德他尼 N-氧化物）。在尿液和粪便中还发现了一种进一步的痕量次要代谢物（葡萄糖醛酸缀合物）。在 21 天内，粪便（44%）和尿液（25%）中约有三分之二的剂量被回收，强调了两种消除途径的重要性。除了 300mg 凡德他尼剂量的 2 名受试者外，所有受试者在研究 A 中报告了不良事件；分别在研究 B 中接受进食和禁食条件下凡德他尼的 12/15（80%）和 14/16（88%）名受试者；以及研究 C 中的 2/4（50%）名受试者。未报告严重不良事件。研究 A 中，凡德他尼剂量增加与收缩压和舒张压的可变增加以及 QTc 间期从基线的可变增加相关。3 名受试者（凡德他尼 300mg）在研究 A 中报告了血尿。在接受凡德他尼治疗的受试者中，血清肌酐略有但持续增加，这在这些研究中观察到。在任何研究中，临床化学、血液学和尿液分析参数、生命体征和心电图均未观察到其他临床重要变化。
确定了健康受试者单次口服凡德他尼后的药代动力学特征，并提出了代谢途径。凡德他尼口服后吸收和消除缓慢，单次口服后 t（½）约为 10 天。吸收程度不受食物存在的影响。在 21 天内，粪便（44%）和尿液（25%）中约有三分之二的剂量被回收。在血浆、尿液和粪便中均检测到未改变的凡德他尼和 N-去甲基和 N-氧化物代谢物。凡德他尼在研究人群中似乎具有良好的耐受性。
