Nguyen Linh, Holland Jaymes, Mamelok Richard, Laberge Marie-Kristine, Grenier Julie, Swearingen Dennis, Armas Danielle, Lacy Steven
Exelixis, Inc., San Francisco, CA, USA.
Mamelok Consulting, Palo Alto, CA, USA.
J Clin Pharmacol. 2015 Nov;55(11):1293-302. doi: 10.1002/jcph.526. Epub 2015 Jun 26.
Cabozantinib is a small molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. Cabozantinib exhibits a pH-dependent solubility profile in vitro. Two phase 1 clinical pharmacology studies were conducted in healthy subjects to evaluate whether factors that may affect cabozantinib solubility and gastric pH could alter cabozantinib bioavailability: a food effect study (study 1) and a drug-drug interaction (DDI) study with the proton pump inhibitor (PPI) esomeprazole (study 2). Following a high-fat meal (study 1), cabozantinib Cmax and AUC were increased (40.5% and 57%, respectively), and the median tmax was delayed by 2 hours. Cabozantinib should thus not be taken with food (patients should not eat for at least 2 hours before and at least 1 hour after administration). In the DDI study (study 2), the 90% confidence intervals (CIs) around the ratio of least-squares means of cabozantinib with esomeprazole versus cabozantinib alone for AUC0-inf were within the 80%-125% limits; the upper 90%CI for Cmax was 125.1%. Because of the low apparent risk of a DDI, concomitant use of PPIs or weaker gastric pH-altering agents with cabozantinib is not contraindicated.
卡博替尼是一种小分子酪氨酸激酶抑制剂，已被批准用于治疗进展性、转移性甲状腺髓样癌患者。卡博替尼在体外表现出pH依赖性溶解度特征。在健康受试者中进行了两项1期临床药理学研究，以评估可能影响卡博替尼溶解度和胃pH值的因素是否会改变卡博替尼的生物利用度：一项食物影响研究（研究1）和一项与质子泵抑制剂（PPI）埃索美拉唑的药物相互作用（DDI）研究（研究2）。高脂餐后（研究1），卡博替尼的Cmax和AUC增加（分别为40.5%和57%），中位tmax延迟2小时。因此，卡博替尼不应与食物同服（患者在给药前至少2小时和给药后至少1小时不应进食）。在DDI研究（研究2）中，卡博替尼与埃索美拉唑联用相对于单独使用卡博替尼的AUC0-inf的最小二乘均值之比的90%置信区间（CI）在80%-125%范围内；Cmax的90%CI上限为125.1%。由于药物相互作用的明显风险较低，卡博替尼与PPI或较弱的胃pH值改变剂同时使用并无禁忌。
