CLINICAL PHARMACOLOGY
Mechanism of Action
Vismodegib is an inhibitor of the Hedgehog pathway. Vismodegib binds to and inhibits Smoothened, a transmembrane protein involved in Hedgehog signal transduction.
Pharmacokinetics
Absorption
Vismodegib is a highly permeable compound with low aqueous solubility (BCS Class 2). The single dose absolute bioavailability of vismodegib is 31.8%. Absorption is saturable as evidenced by the lack of dose proportional increase in exposure after a single dose of 270 mg or 540 mg vismodegib. ERIVEDGE capsule may be taken without regard to meals because the systemic exposure of vismodegib at steady state is not affected by food.
Distribution
The volume of distribution of vismodegib ranges from 16.4 to 26.6 L. Vismodegib plasma protein binding in patients is greater than 99%. Vismodegib binds to both human serum albumin and alpha-1-acid glycoprotein (AAG) and binding to AAG is saturable.
Metabolism
Greater than 98% of the total circulating drug-related components are the parent drug. Metabolic pathways of vismodegib in humans include oxidation, glucuronidation, and pyridine ring cleavage. The two most abundant oxidative metabolites recovered in feces are produced in vitro by recombinant CYP2C9 and CYP3A4/5.
Elimination
Vismodegib and its metabolites are eliminated primarily by the hepatic route with 82% of the administered dose recovered in the feces and 4.4% recovered in urine. The estimated elimination half-life (t1/2) of vismodegib is 4 days after continuous once-daily dosing and 12 days after a single dose.
Pharmacokinetics in Specific Populations
Hepatic Impairment: The effect of hepatic impairment on the systemic exposure of vismodegib has not been studied.
Renal Impairment: The effect of renal impairment on the systemic exposure of vismodegib has not been studied.
Population pharmacokinetic analyses showed that weight (range: 41-140 kg), age (range: 26-89 years), creatinine clearance (range: 30 to 80 mL/min), and sex do not have a clinically meaningful influence on the systemic exposure of vismodegib.
Cardiac Electrophysiology
In a thorough QTc study in 60 healthy subjects, there was no effect of therapeutic doses of ERIVEDGE on the QTc interval.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies with vismodegib have not been conducted. Pilomatricoma (a benign cutaneous neoplasm) was observed in rats administered oral vismodegib for 26 weeks at 100 mg/kg/day (approximately 0.8 times the systemic exposure (AUC) in patients at the recommended human dose).
Vismodegib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human chromosomal aberration assay in human peripheral blood lymphocytes or in the in vivo rat bone marrow micronucleus assay.
Studies to assess the potential of vismodegib to affect fertility have not been conducted; however, data from repeat-dose toxicology studies in rats and dogs indicate that male and female reproductive function and fertility may be impaired in patients receiving ERIVEDGE capsule. In a 26-week toxicology study in rats, a relative decrease in percent motile sperm was observed at ≥ 15 mg/kg/day (approximately ≥ 0.3 times the AUC in patients at the recommended human dose). In dogs, increased numbers of degenerating germ cells and hypospermia were observed in young animals administered oral vismodegib for 4 weeks at ≥ 50 mg/kg/day (approximately ≥ 2 times the AUC in patients at the recommended human dose). No corresponding findings were observed in sexually mature dogs at similar doses in 13-week and 26-week toxicology studies. A decrease in the number of corpora lutea was observed in female rats administered oral vismodegib for 26 weeks at 100 mg/kg/day (approximately 0.8 times the AUC in patients at the recommended human dose).
Animal Toxicology
Neurologic effects characterized as limb or body tremors or twitching were observed in rats administered oral vismodegib for 4 weeks or longer at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the AUC in patients at the recommended human dose). These observations resolved upon discontinuation of dosing and were not associated with microscopic findings.
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