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.

Metabolism and Disposition of Cabozantinib in Healthy Male Volunteers and Pharmacologic Characterization of Its Major Metabolites

“…CYP isozyme inhibition kinetics determined using human hepatic microsomal incubations for EXEL-1644, the metabolite with the highest plasma exposure, are presented in Table 3; CYP inhibition data for parent cabozantinib are provided for reference (Nguyen et al, 2015). EXEL-1644 and cabozantinib are both more potent direct inhibitors of CYP2C8 (K i = 1.1 and 4.6 mM, respectively) than of CYP2C9 (K i = 32.5 and 10.4 mM, respectively).…”

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

“…For instance, axitinib inhibits CYP2C8 in vitro with a K i of 0.2-0.5 mM (I/K i = 0.3-0.9), but it did not alter paclitaxel plasma concentrations in patients (FDA, 2012f;Wang et al, 2014a). Similarly, cabozantinib is a noncompetitive inhibitor of CYP2C8 in vitro (K i = 4.6 mM, I/K i = 0.7), but the in vivo pharmacokinetics of rosiglitazone was not affected by cabozantinib (FDA, 2012c;Nguyen et al, 2015). The inhibition of CYP2C8 by pazopanib (K i of 3.7 mM, I/K i = 35) may be of clinical relevance (FDA, 2009d;Tan et al, 2014;Wang et al, 2014b).…”

Effect of Renal and Hepatic Impairment on the Pharmacokinetics of Cabozantinib

“…In healthy subjects, coadministration of the strong CYP3A inhibitor ketoconazole increased plasma cabozantinib exposure (AUC) by 38%, whereas coadministration of the strong CYP3A inducer rifampin decreased plasma cabozantinib exposure by 77%. 4 A high-fat meal was also shown to increase cabozantinib plasma C max and overall exposure (AUC 0-Ý ) by 41% and 57%, respectively, in healthy subjects. 5 Hepatic and renal disease are intrinsic factors that may affect the absorption, metabolism, disposition (eg, protein binding), and elimination of orally administered anticancer drugs.…”