Evaluation of the effect of food and gastric pH on the single-dose pharmacokinetics of cabozantinib in healthy adult subjects

• Published in: Journal of clinical pharmacology 2015-11, Vol.55 (11), p.1293-1302
• Main Authors: Nguyen, Linh, Holland, Jaymes, Mamelok, Richard, Laberge, Marie-Kristine, Grenier, Julie, Swearingen, Dennis, Armas, Danielle, Lacy, Steven
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Anilides - adverse effects; Anilides - blood; Anilides - pharmacokinetics; Biological Availability; cabozantinib; Confidence intervals; Cross-Over Studies; Drug Interactions; Esomeprazole - pharmacology; Female; Food; food effect; Healthy Volunteers; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; pharmacokinetics; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - blood; Protein Kinase Inhibitors - pharmacokinetics; proton pump inhibitor; Proton Pump Inhibitors - pharmacology; Pyridines - adverse effects; Pyridines - blood; Pyridines - pharmacokinetics; Stomach - metabolism; Young Adult
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1002/jcph.526

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.