Clinical Pharmacokinetics and Pharmacodynamics of Cabozantinib

Cabozantinib inhibits receptor tyrosine kinases involved in tumor angiogenesis and metastasis. The capsule formulation (Cometriq((R))) is approved for the treatment of progressive metastatic medullary thyroid cancer at a 140-mg free base equivalent dose. The tablet formulation (Cabometyx (TM), 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 (similar to 120 h) and accumulates similar to 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.