title: Pharmacokinetic (PK) drug interaction studies of cabozantinib: Effect of CYP3A inducer rifampin and inhibitor ketoconazole on cabozantinib plasma PK and effect of cabozantinib on CYP2C8 probe substrate rosiglitazone plasma PK.
abstract: Cabozantinib is a small-molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. In vitro data indicate that (1) cytochrome P450 (CYP) 3A4 is the primary CYP isoenzyme involved in the metabolism of cabozantinib, and (2) CYP2C8 is the CYP isoenzyme most potently inhibited by cabozantinib with potential for in vivo inhibition at clinically relevant plasma exposures. Pharmacokinetic (PK) drug-drug interactions (DDIs) were evaluated clinically between cabozantinib and (1) a CYP3A inducer (rifampin) in healthy volunteers, (2) a CYP3A inhibitor (ketoconazole) in healthy volunteers, and (3) a CYP2C8 substrate (rosiglitazone) in patients with solid tumors. Compared with cabozantinib given alone, coadministration with rifampin resulted in a 4.3-fold higher plasma clearance (CL/F) of cabozantinib and a 77% decrease in cabozantinib plasma AUC0-inf , whereas coadministration with ketoconazole decreased cabozantinib CL/F by 29% and increased cabozantinib AUC0-inf by 38%. Chronic coadministration with cabozantinib resulted in no significant effect on rosiglitazone plasma Cmax , AUC0-24 , or AUC0-inf . In summary, chronic use of strong CYP3A inducers and inhibitors should be avoided when cabozantinib is administered, and cabozantinib at clinically relevant exposures is not anticipated to markedly affect the PK of concomitant medications via CYP enzyme inhibition.
authors: Exelixis, Inc., So. San Francisco, CA, USA.
authors: Linh
authors: L
authors: Nguyen
authors: Exelixis, Inc., So. San Francisco, CA, USA.
authors: Jaymes
authors: J
authors: Holland
authors: Exelixis, Inc., So. San Francisco, CA, USA.
authors: Dale
authors: D
authors: Miles
authors: Celerion, Montreal, Quebec, Canada.
authors: Caroline
authors: C
authors: Engel
authors: Celerion, Montreal, Quebec, Canada.
authors: Natacha
authors: N
authors: Benrimoh
authors: Celerion, Tempe, AZ, USA.
authors: Terry
authors: T
authors: O'Reilly
authors: Exelixis, Inc., So. San Francisco, CA, USA.
authors: Steven
authors: S
authors: Lacy
mesh_terms: D000813:Anilides / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D065727:Cytochrome P-450 CYP2C8 / Q000378:metabolism; D065701:Cytochrome P-450 CYP3A Inducers / Q000008:administration & dosage / Q000493:pharmacokinetics; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000097:blood / Q000493:pharmacokinetics; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics; D007654:Ketoconazole / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D007004:Hypoglycemic Agents; D011725:Pyridines; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C558660:cabozantinib; D065727:Cytochrome P-450 CYP2C8; D020794:Receptor Protein-Tyrosine Kinases; D007654:Ketoconazole; D012293:Rifampin
keywords: CYP2C8; CYP3A4; cabozantinib; drug-drug interaction; pharmacokinetics