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.

Autor: Nguyen L; Exelixis, Inc., So. San Francisco, CA, USA., Holland J; Exelixis, Inc., So. San Francisco, CA, USA., Miles D; Exelixis, Inc., So. San Francisco, CA, USA., Engel C; Celerion, Montreal, Quebec, Canada., Benrimoh N; Celerion, Montreal, Quebec, Canada., O'Reilly T; Celerion, Tempe, AZ, USA., Lacy S; Exelixis, Inc., So. San Francisco, CA, USA.
Jazyk: angličtina
Zdroj: Journal of clinical pharmacology [J Clin Pharmacol] 2015 Sep; Vol. 55 (9), pp. 1012-23. Date of Electronic Publication: 2015 Jun 02.
DOI: 10.1002/jcph.510
Abstrakt: 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.
(© 2015, The American College of Clinical Pharmacology.)
Databáze: MEDLINE
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