COMETRIQ Hard capsule Ref.[116727] Active ingredients: Cabozantinib

Absorption

Following oral administration of cabozantinib, peak cabozantinib plasma concentrations are reached at 2 to 5 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 (CABOMETYX) compared to the capsule formulation (COMETRIQ) was observed. AUC were similar between cabozantinib tablet (CABOMETYX) and capsule (COMETRIQ) formulations (<10% difference).

Distribution

Cabozantinib is highly protein bound in vitro in human plasma (≥99.7%). Based on the population-pharmacokinetic (PK) model, the volume of distribution (V/F) is approximately 349 L (SE: ± 2.73%). 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

The plasma terminal half-life of cabozantinib in single dose studies in healthy volunteers is approximately 120 hours. Mean clearance (CL/F) at steady-state in cancer patients was estimated to be 4.4 L/hr in a population PK analysis. 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

Results from a study in patients with renal impairment indicate that 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. Patients with severe renal impairment have not been studied.

Hepatic impairment

Results from a study in patients with hepatic impairment indicate that exposure (AUC_0-inf) increased by 81% and 63% in subjects with mild and moderate hepatic impairment, respectively (90% CI for AUC_0-inf: 121.44% to 270.34% for mild and 107.37% to 246.67% for moderate). Patients with severe hepatic impairment have not been studied.

Race

No data are available to determine a difference in PK 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 observe 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 pediatric 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 bile duct hyperplasia. Findings in uterus/ovaries and decreased haematopoiesis appeared to be transient, while effects on bone parameters and liver pigmentation were sustained. Evaluations in juvenile rats (comparable to a <2 year old pediatric population) have not been performed.