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Evaluation of the effect of food and gastric pH on the single‐dose pharmacokinetics of cabozantinib in healthy adult subjects
Author(s) -
Nguyen Linh,
Holland Jaymes,
Mamelok Richard,
Laberge MarieKristine,
Grenier Julie,
Swearingen Dennis,
Armas Danielle,
Lacy Steven
Publication year - 2015
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.526
Subject(s) - cabozantinib , pharmacokinetics , esomeprazole , bioavailability , tyrosine kinase inhibitor , medicine , pharmacology , medullary thyroid cancer , gastroenterology , concomitant , drug interaction , drug , cancer , thyroid cancer
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 C max and AUC were increased (40.5% and 57%, respectively), and the median t max 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 AUC 0–inf were within the 80%–125% limits; the upper 90%CI for C max 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.