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.

The identification of patient‐specific mutations reveals dual pathway activation in most patients with melanoma and activated receptor tyrosine kinases in BRAF/NRAS wild‐type melanomas

“…Although RET, FGFR1, and MET are not considered melanoma targets, affected patients may benefit from RTK inhibitors. The RET‐targeting multikinase inhibitor cabozantinib is clinically approved for the treatment of renal cell carcinoma and medullary thyroid carcinoma . In addition to RET, cabozantinib also inhibits MET and KIT.…”

A population pharmacokinetic model of cabozantinib in healthy volunteers and patients with various cancer types

“…However, only 1.4% of patients (3 of 207 total) were reported to have used a concomitant strong CYP3A4 inducer in the MTC phase III study of cabozantinib [11]. Cabozantinib is also a substrate of efflux transporter MRP2 [25], so concomitant administration of an MRP2 inducer could potentially increase cabozantinib clearance by enhancing hepatic and/or intestinal drug MRP2-mediated transport activity. Although overall use of concomitant MRP2 inducers was not documented for MTC patients in study XL184-301, only 5.5% of MTC subjects (12 of 219) administered cabozantinib were reported to have received MRP2 inducer (and moderate CYP3A4 inducer) dexamethasone.…”

“…The approved cabozantinib dose for MTC patients (140-mg) is higher than the dose approved for RCC patients and dose generally administered to non-MTC patient populations (60-mg), and steady-state CL/ F in the MTC popPK analysis (4.4 L/h) was higher than that determined in the RCC popPK analysis (2.2 L/h). However, no decrease in cabozantinib oral bioavailability was evident in a cross-study analysis indicating generally dose-linear PK for tablet and capsule formulations over a broad dose range (20–140 mg) [25]. In addition, lower cabozantinib exposures associated with higher relative CL/ F in MTC patients were only observed at steady state (day 29) and not at day 1.…”

“…As cabozantinib has a relatively long plasma terminal half-life (HV mean: 118 h [25]), plasma clearance could have been underestimated in the MTC popPK analysis based on a more limited PK data collection of terminal elimination phase. However, the integrated popPK model developed subsequently included exposure data from patients with different tumor types and HVs; the addition of all covariates, including demographic (age, weight sex, and race) and population (RCC, CRPC, MTC, GB, and advanced malignancies) on both CL/ F and Vc/ F resulted in an adequate fit to the data.…”

A dose finding clinical trial of cabozantinib (XL184) administered in combination with abiraterone acetate in metastatic castration‐resistant prostate cancer

“…CYP3A4/5 is the major cytochrome P450 (CYP) isozyme involved in the hepatic metabolism of both abiraterone and cabozantinib in humans, with minimal involvement of other CYP isozymes. 24,46 In vitro studies using human hepatic microsomes showed that abiraterone is a moderate Palmar-plantar erythrodysesthesia syndrome 3 (11) ALT 2 (7) Musculoskeletal and connective tissue 3 (11) Lipase increase 2 (7) Anemia 2 (7) Thromboembolic event 2 (7) ALT 2 (7) Thromboembolic event 2 (7) inhibitor of CYP3A4/5 and that cabozantinib inhibits the isozyme weakly.…”