title: Clinical Pharmacokinetics and Pharmacodynamics of Cabozantinib.
abstract: Cabozantinib inhibits receptor tyrosine kinases involved in tumor angiogenesis and metastasis. The capsule formulation (Cometriq®) is approved for the treatment of progressive metastatic medullary thyroid cancer at a 140-mg free base equivalent dose. The tablet formulation (Cabometyx™, 60-mg free base equivalent dose) is approved for the treatment of renal cell carcinoma following anti-angiogenic therapy. Cabozantinib displays a long terminal plasma half-life (~120 h) and accumulates ~fivefold by day 15 following daily dosing based on area under the plasma concentration-time curve (AUC). Four identified inactive metabolites constitute >65 % of total cabozantinib-related AUC following a single 140-mg free base equivalent dose. Cabozantinib AUC was increased by 63-81 % or 7-30 % in subjects with mild/moderate hepatic or renal impairment, respectively; by 34-38 % with concomitant cytochrome P450 3A4 inhibitor ketoconazole; and by 57 % following a high-fat meal. Cabozantinib AUC was decreased by 76-77 % with concomitant cytochrome P450 3A4 inducer rifampin, and was unaffected following administration of proton pump inhibitor esomeprazole. Cabozantinib is a potent in vitro inhibitor of P-glycoprotein, and multidrug and toxin extrusion transporter 1 and 2-K, and is a substrate for multidrug resistance protein 2. No clinically significant covariates affecting cabozantinib pharmacokinetics were identified in a population pharmacokinetic analysis. Patients with medullary thyroid cancer with low model-predicted apparent clearance were more likely to dose hold/reduce cabozantinib early, and had a lower average dose through day 85. However, longitudinal tumor modeling suggests that cabozantinib dose reductions from 140 to 60 mg/day did not markedly reduce tumor growth inhibition in medullary thyroid cancer patients.
authors.affiliation: Exelixis Inc., 210 East Grand Avenue, South San Francisco, CA, 94080-0511, USA. slacy@exelixis.com.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Lacy
authors.affiliation: Exelixis Inc., 210 East Grand Avenue, South San Francisco, CA, 94080-0511, USA.|Genentech Inc., South San Francisco, CA, USA.
authors.forename: Dale R
authors.initials: DR
authors.lastname: Miles
authors.affiliation: Exelixis Inc., 210 East Grand Avenue, South San Francisco, CA, 94080-0511, USA.|Medivation Inc., San Francisco, CA, USA.
authors.forename: Linh T
authors.initials: LT
authors.lastname: Nguyen
mesh_terms: D000813:Anilides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000097:blood* / Q000188:drug therapy; D002986:Clinical Trials as Topic / Q000379:methods; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007680:Kidney Neoplasms / Q000097:blood* / Q000188:drug therapy; D011725:Pyridines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000097:blood* / Q000188:drug therapy
chemical_list: D000813:Anilides; D011725:Pyridines; C558660:cabozantinib; D020794:Receptor Protein-Tyrosine Kinases