Cabozantinib

Cabozantinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumour growth and angiogenesis, pathologic bone remodeling, drug resistance, and metastatic progression of cancer. Cabozantinib was evaluated for its inhibitory activity against a variety of kinases and was identified as an inhibitor of MET (hepatocyte growth factor receptor protein) and VEGF (vascular endothelial growth factor) receptors. In addition, cabozantinib inhibits other tyrosine kinases including the GAS6 receptor (AXL), RET, ROS1, TYRO3, MER, the stem cell factor receptor (KIT), TRKB, Fms-like tyrosine kinase-3 (FLT3), and TIE-2.

Pharmacodynamic effects

Cabozantinib exhibited dose-related tumour growth inhibition, tumour regression, and/or inhibited metastasis in a broad range of preclinical tumour models.

Cardiac electrophysiology

An increase from baseline in corrected QT interval by Fridericia (QTcF) of 10–15 ms on Day 29 (but not on Day 1) following initiation of cabozantinib treatment (at a dose of 140 mg qd) was observed in a controlled clinical study in medullary thyroid cancer patients. This effect was not associated with a change in cardiac wave form morphology or new rhythms. No cabozantinib-treated subjects in this study had a confirmed QTcF >500 ms, nor did any cabozantinib-treated subjects in the RCC or HCC studies (at a dose of 60 mg).

Absorption

Following oral administration of cabozantinib, peak cabozantinib plasma concentrations are reached at 3 to 4 hours post-dose. Plasma-concentration time profiles show a second absorption peak approximately 24 hours after administration, which suggests that cabozantinib may undergo enterohepatic recirculation.

Repeat daily dosing of cabozantinib at 140 mg for 19 days resulted in an approximately a 4- to 5-fold mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steady state is achieved by approximately Day 15.

A high-fat meal moderately increased C_max and AUC values (41% and 57%, respectively) relative to fasted conditions in healthy volunteers administered a single 140 mg oral cabozantinib dose. There is no information on the precise food-effect when taken 1 hour after administration of cabozantinib.

Bioequivalence could not be demonstrated between the cabozantinib capsule and tablet formulations following a single 140 mg dose in healthy subjects. A 19% increase in the C_max of the tablet formulation compared to the capsule formulation was observed. A less than 10% difference in the AUC was observed between cabozantinib tablet and capsule formulations.

Distribution

Cabozantinib is highly protein bound in vitro in human plasma (≥ 99.7%). Based on the population- pharmacokinetic (PK) model, the volume of distribution of the central compartment (Vc/F) was estimated to be 212 L. Protein binding was not altered in subjects with mild or moderately impaired renal or hepatic function.

Biotransformation

Cabozantinib was metabolized in vivo. Four metabolites were present in plasma at exposures (AUC) greater than 10% of parent: XL184-N-oxide, XL184 amide cleavage product, XL184 monohydroxy sulfate, and 6-desmethyl amide cleavage product sulfate. Two non-conjugated metabolites (XL184- N-oxide and XL184 amide cleavage product), which possess <1% of the on-target kinase inhibition potency of parent cabozantinib, each represent <10% of total drug-related plasma exposure.

Cabozantinib is a substrate for CYP3A4 metabolism in vitro, as a neutralizing antibody to CYP3A4 inhibited formation of metabolite XL184 N-oxide by >80% in a NADPH-catalyzed human liver microsomal (HLM) incubation; in contrast, neutralizing antibodies to CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation. A neutralizing antibody to CYP2C9 showed a minimal effect on cabozantinib metabolite formation (ie, a <20% reduction).

Elimination

In a population PK analysis of cabozantinib using data collected from 1883 patients and 140 healthy volunteers following oral administration of a range of doses from 20 to 140 mg, the plasma terminal half-life of cabozantinib is approximately 110 hours. Mean clearance (CL/F) at steady-state was estimated to be 2.48 L/hr . Within a 48-day collection period after a single dose of ¹⁴C-cabozantinib in healthy volunteers, approximately 81% of the total administered radioactivity was recovered with 54% in faeces and 27% in urine.

Pharmacokinetics in special patient populations

Renal impairment

In a renal impairment study conducted with a single 60 mg dose of cabozantinib, the ratios of geometric LS mean for plasma cabozantinib, C_max and AUC_0-inf were 19% and 30% higher, for subjects with mild renal impairment (90% CI for C_max 91.60% to 155.51%; AUC_0-inf 98.79% to 171.26%) and 2% and 6-7% higher (90% CI for C_max 78.64% to 133.52%; AUC_0-inf 79.61% to 140.11%), for subjects with moderate renal impairment compared to subjects with normal renal function. Subjects with severe renal impairment have not been studied.

Hepatic impairment

Based on an integrated population pharmacokinetic analysis of cabozantinib in healthy subjects and cancer patients (including HCC), no clinically significant difference in the mean cabozantinib plasma exposure was observed amongst subjects with normal liver function (n=1425) and mild hepatic impairment (n=558). There is limited data in patients with moderate hepatic impairment (n=15) as per NCI-ODWG (National Cancer Institute – Organ Dysfunction working Group) criteria. The pharmacokinetics of cabozantinib was not evaluated in patients with severe hepatic impairment.

Race

A population PK analysis did not identify clinically relevant differences in PK of cabozantinib based on race.

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:

In rat and dog repeat-dose toxicity studies up to 6 months duration, target organs for toxicity were GI tract, bone marrow, lymphoid tissues, kidney, adrenal and reproductive tract tissues. The no observed adverse effect level (NOAEL) for these findings were below human clinical exposure levels at intended therapeutic dose.

Cabozantinib has shown no mutagenic or clastogenic potential in a standard battery of genotoxicity assays. The carcinogenic potential of cabozantinib has been evaluated in two species: rasH2 transgenic mice and Sprague-Dawley rats. In the 2-year rat carcinogenicity study, cabozantinib-related neoplastic findings consisted of an increased incidence of benign pheochromocytoma, alone or in combination with malignant pheochromocytoma/complex malignant pheochromocytoma of the adrenal medulla in both sexes at exposures well below the intended exposure in humans. The clinical relevance of the observed neoplastic lesions in rats is uncertain, but likely to be low.

Cabozantinib was not carcinogenic in the rasH2 mouse model at a slightly higher exposure than the intended human therapeutic exposure.

Fertility studies in rats have shown reduced male and female fertility. Further, hypospermatogenesis was observed in male dogs at exposure levels below human clinical exposure levels at intended therapeutic dose.

Embryo-foetal development studies were performed in rats and rabbits. In rats, cabozantinib caused postimplantation loss, foetal oedema, cleft palate/lip, dermal aplasia and kinked or rudimentary tail. In rabbits, cabozantinib produced foetal soft tissue changes (reduced spleen size, small or missing intermediate lung lobe) and increased foetal incidence of total malformations. NOAEL for embryo- foetal toxicity and teratogenic findings were below human clinical exposure levels at intended therapeutic dose.

Juvenile rats (comparable to a >2 year-old paediatric population) administered cabozantinib showed increased WBC parameters, decreased haematopoiesis, pubescent/immature female reproductive system (without delayed vaginal opening), tooth abnormalities, reduced bone mineral content and density, liver pigmentation and lymph node lymphoid hyperplasia. Findings in uterus/ovaries and decreased haematopoiesis appeared to be transient, while effects on bone parameters and liver pigmentation were sustained. Juvenile rats (correlating to a <2-year paediatric population) showed similar treatment-related findings but appeared to be more sensitive to cabozantinib-related toxicity at comparable dose levels.