title: Evaluation of the effect of food and gastric pH on the single-dose pharmacokinetics of cabozantinib in healthy adult subjects.
abstract: 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.
authors.affiliation: Exelixis, Inc., San Francisco, CA, USA.
authors.forename: Linh
authors.initials: L
authors.lastname: Nguyen
authors.affiliation: Exelixis, Inc., San Francisco, CA, USA.
authors.forename: Jaymes
authors.initials: J
authors.lastname: Holland
authors.affiliation: Mamelok Consulting, Palo Alto, CA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Mamelok
authors.affiliation: Celerion, Montreal, QC, Canada.
authors.forename: Marie-Kristine
authors.initials: MK
authors.lastname: Laberge
authors.affiliation: Celerion, Montreal, QC, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Grenier
authors.affiliation: Celerion, Tempe, AZ, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Swearingen
authors.affiliation: Celerion, Tempe, AZ, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Armas
authors.affiliation: Exelixis, Inc., San Francisco, CA, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Lacy
mesh_terms: D000293:Adolescent; D000328:Adult; D000813:Anilides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D018592:Cross-Over Studies; D004347:Drug Interactions; D064098:Esomeprazole / Q000494:pharmacology*; D005260:Female; D005502:Food; D005753:Gastric Mucosa / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000813:Anilides; D047428:Protein Kinase Inhibitors; D054328:Proton Pump Inhibitors; D011725:Pyridines; C558660:cabozantinib; D064098:Esomeprazole
keywords: cabozantinib; drug interactions; food effect; pharmacokinetics; proton pump inhibitor