Vismodegib

log Kow = 2.7

2.84

Breast Feeding; Lactation; Antineoplastic Agents; Enzyme Inhibitors; Protein Kinase Inhibitors; Signal Transduction Inhibitors

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

3.8

pKa = 3.8 (pyridinium cation)

Danger

H302+H312+H332 (25%): Harmful if swallowed, in contact with skin or if inhaled [Warning Acute toxicity, oral; acute toxicity, dermal; acute toxicity, inhalation]

P203, P260, P261, P264, P264+P265, P270, P271, P273, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P317, P318, P319, P321, P330, P332+P317, P337+P317, P362+P364, P391, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 4 reports by companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including vismodegib, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Drugs that alter the pH of the upper GI tract (e.g. proton pump inhibitors, H2-receptor antagonists, and antacids) may alter the solubility of vismodegib and reduce its bioavailability. However, no formal clinical study has been conducted to evaluate the effect of gastric pH altering agents on the systemic exposure of vismodegib. Increasing the dose of Erivedge when coadministered with such agents is not likely to compensate for the loss of exposure. When Erivedge is coadministered with a proton pump inhibitor, H2-receptor antagonist or antacid, systemic exposure of vismodegib may be decreased and the effect on efficacy of Erivedge is unknown.

In vitro studies indicate that vismodegib is a substrate of the efflux transporter P-glycoprotein (P-gp). When Erivedge is coadministered with drugs that inhibit P-gp (e.g. clarithromycin, erythromycin, azithromycin), systemic exposure of vismodegib and incidence of adverse events of Erivedge may be increased.

Vismodegib elimination involves multiple pathways. Vismodegib is predominantly excreted as an unchanged drug. Several minor metabolites are produced by multiple CYP enzymes. Although vismodegib is a substrate of CYP2C9 and CYP3A4 in vitro, CYP inhibition is not predicted to alter vismodegib systemic exposure since similar steady-state plasma vismodegib concentrations were observed in patients in clinical trials concomitantly treated with CYP3A4 inducers (i.e., carbamazepine, modafinil, phenobarbital) and those concomitantly treated with CYP3A4 inhibitors (i.e., erythromycin, fluconazole).

Vismodegib, a first-in-class oral hedgehog pathway inhibitor, is an effective treatment for advanced basal cell carcinoma. Based on in vitro data, a clinical drug-drug interaction (DDI) assessment of cytochrome P450 (CYP) 2C8 was necessary; vismodegib's teratogenic potential warranted a DDI study with oral contraceptives (OCs). This single-arm, open-label study included two cohorts of patients with locally advanced or metastatic solid malignancies [Cohort 1: rosiglitazone 4 mg (selective CYP2C8 probe); Cohort 2: OC (norethindrone 1 mg/ethinyl estradiol 35 ug; CYP3A4 substrate)]. On Day 1, patients received rosiglitazone or OC. On Days 2-7, patients received vismodegib 150 mg/day. On Day 8, patients received vismodegib plus rosiglitazone or OC. The effect of vismodegib on rosiglitazone and OC pharmacokinetic parameters (primary objective) was evaluated through pharmacokinetic sampling over a 24-h period (Days 1 and 8). RESULTS: The mean + or - SD vismodegib steady-state plasma concentration (Day 8, N = 51) was 20.6 + or - 9.72 uM (range 7.93-62.4 uM). Rosiglitazone AUC(0-inf) and C(max) were similar with concomitant vismodegib [=8% change in geometric mean ratios (GMRs); N = 24]. Concomitant vismodegib with OC did not affect ethinyl estradiol AUC(0-inf) and C(max) (=5% change in GMRs; N = 27); norethindrone C(max) and AUC(0-inf) GMRs were higher (12 and 23%, respectively) with concomitant vismodegib. CONCLUSIONS: This DDI study in patients with cancer demonstrated that systemic exposure of rosiglitazone (a CYP2C8 substrate) or OC (ethinyl estradiol/norethindrone) is not altered with concomitant vismodegib. Overall, there appears to be a low potential for DDIs when vismodegib is co-administered with other medications.

Most clinical trials of vismodegib included few patients, and rates of liver tests abnormalities were usually not reported. The product label for vismodegib includes no mention serum enzyme elevations or need for monitoring of routine liver tests. In a subsequent review of all published studies of vismodegib, liver enzyme elevations were said to occur in 1.4% of a total of 363 patients treated. Since its approval and more general use, reports of clinically apparent liver injury linked to vismodegib have appeared, and the product label now mentions adverse events of hepatotoxicity and Stevens Johnson syndrome in post marketing reports. In one published report, an elderly man presented with fatigue, nausea, and jaundice 41 days after starting vismodegib with a cholestatic pattern of serum enzyme elevations and rapid improvement on stopping (Case 1). In addition, review of 7 years of spontaneous adverse event reporting to the FDA revealed 94 reports of hepatotoxicity during vismodegib therapy, including 20 that were considered serious and 4 that resulted in hepatic failure. The latency to onset was typically within 2 to 12 weeks of starting vismodegib and the pattern of injury was typically cholestatic, although less commonly hepatocellular. Autoimmune features are not common but in several reports there were features of immune allergic reactions (rash, eosinophilia, fever). Thus, clinically apparent liver injury from vismodegib occurs, but is somewhat rare.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 230(SRC), determined from a log Kow of 2.70(2) and a regression-derived equation(3), indicates that vismodegib is expected to have moderate mobility in soil(SRC). Volatilization of vismodegib from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.6X10-17 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Vismodegib is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 7.6X10-14 mm Hg at 25 °C(SRC), determined from a fragment constant method(3). Biodegrataion data in soil were not available(SRC, 2013).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 230(SRC), determined from a log Kow of 2.70(2) and a regression-derived equation(3), indicates that vismodegib is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(4) based upon an estimated Henry's Law constant of 1.6X10-17 atm-cu m/mole(SRC), developed using a fragment constant estimation method(5). According to a classification scheme(6), an estimated BCF of 30(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data in water were not available(SRC, 2013).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), vismodegib, which has an estimated vapor pressure of 7.6X10-14 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase vismodegib may be removed from the air by wet and dry deposition(SRC). Vismodegib contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

The adverse effects of vismodegib have been a limiting factor for the medication. All patients in the ERIVANCE trial experienced at least one adverse event. In the ERIVANCE trial, 57% had a mild (grade 1) or moderate (grade 2) adverse event. A total of 13 individuals (12%) had an adverse event that ultimately led to the discontinuation of vismodegib.

The Koc of vismodegib is estimated as 230(SRC), using a log Kow of 2.70(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that vismodegib is expected to have moderate mobility in soil. However, aromatic amines are expected to bind strongly to humus or organic matter in soils due to the high reactivity of the aromatic amino group(4,5), suggesting that mobility may be much lower in some soils(SRC).

Drug Induced Liver Injury Rank (DILIrank 2.0)

Vismodegib

Ambiguous-DILI-concern

3

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

An estimated BCF of 30 was calculated in fish for vismodegib(SRC), using a log Kow of 2.70(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC).

The Henry's Law constant for vismodegib is estimated as 1.6X10-17 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that vismodegib is expected to be essentially nonvolatile from water or moist soil surfaces(2). Vismodegib is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 7.6X1014 mm Hg(SRC), determined from a fragment constant method(3).

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at > or = 50 mg/kg/day (approximately > or = 0.4 times the systemic exposure (AUC) in patients at the recommended human dose). Abnormalities in growing incisor teeth (including degeneration/necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at > or = 15 mg/kg/day (approximately > or = 0.2 times the AUC in patients at the recommended human dose).

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Neurologic effects characterized as limb or body tremors or twitching were observed in rats administered oral vismodegib for 4 weeks or longer at > or = 50 mg/kg/day (approximately > or = 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.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ 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).

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ 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 > or = 15 mg/kg/day (approximately > or > or = 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 > or = 50 mg/kg/day (approximately > or = 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).

For more Non-Human Toxicity Excerpts (Complete) data for Vismodegib (6 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including vismodegib, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

L01XX43

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

Vismodegib selectively binds to and inhibits the transmembrane protein smoothened homologue (SMO) to inhibit the Hedgehog signalling pathway. Following 7 days of 150 mg once-daily dosing, the use of vismodegib was not associated with a clinically significant QT interval prolongation. Vismodegib can cause embryo-fetal death or severe birth defects, as well as severe cutaneous adverse reactions and musculoskeletal adverse reactions. In pediatric patients given vismodegib, premature fusion of the epiphyses has been reported.

During embryogenesis, the Hedgehog signaling pathway plays an important role in cell growth, differentiation apoptosis and self-renewal. After this developmental stage, the Hedgehog signaling pathway is silenced in all cells and tissues, except for hair, skin and stem cells. Mutations on elements of the Hedgehog signaling pathway may result in uncontrolled proliferation of basal skin cells, and dysregulated or aberrant Hedgehog signaling has been associated with the pathogenesis of basal cell carcinoma. Therefore, drugs that target and block this pathway, such as vismodegib, may be used to treat this condition. Vismodegib binds to and inhibits the transmembrane protein smoothened homologue (SMO), a protein that leads to the activation and nuclear translocation of several factors involved in the Hedgehog signaling pathway, inhibiting the activation of downstream Hedgehog target genes.

Vismodegib is an inhibitor of the Hedgehog pathway. Vismodegib binds to and inhibits Smoothened, a transmembrane protein involved in Hedgehog signal transduction.

Recent evidence from in vitro and in vivo studies has demonstrated that aberrant reactivation of the Sonic Hedgehog (SHH) signaling pathway regulates genes that promote cellular proliferation in various human cancer stem cells (CSCs). Therefore, the chemotherapeutic agents that inhibit activation of Gli transcription factors have emerged as promising novel therapeutic drugs for pancreatic cancer. GDC-0449 (Vismodegib), orally administrable molecule belonging to the 2-arylpyridine class, inhibits SHH signaling pathway by blocking the activities of Smoothened. The objectives of this study were to examine the molecular mechanisms by which GDC-0449 regulates human pancreatic CSC characteristics in vitro. GDC-0499 inhibited cell viability and induced apoptosis in three pancreatic cancer cell lines and pancreatic CSCs. This inhibitor also suppressed cell viability, Gli-DNA binding and transcriptional activities, and induced apoptosis through caspase-3 activation and PARP cleavage in pancreatic CSCs. GDC-0449-induced apoptosis in CSCs showed increased Fas expression and decreased expression of PDGFRa. Furthermore, Bcl-2 was down-regulated whereas TRAIL-R1/DR4 and TRAIL-R2/DR5 expression was increased following the treatment of CSCs with GDC-0449. Suppression of both Gli1 plus Gli2 by shRNA mimicked the changes in cell viability, spheroid formation, apoptosis and gene expression observed in GDC-0449-treated pancreatic CSCs. Thus, activated Gli genes repress DRs and Fas expressions, up-regulate the expressions of Bcl-2 and PDGFRa and facilitate cell survival. These data suggest that GDC-0499 can be used for the management of pancreatic cancer by targeting pancreatic CSCs.

Hedgehog (Hh) signaling is involved in the pathogenesis of liver fibrosis. It has been previously shown that Hh-inhibitor cyclopamine (CYA) can reduce liver fibrosis in rats. However, CYA is not stable in vivo, which limits its clinical application. This study compares the antifibrotic potential of two known Hh antagonists, vismodegib (GDC-0449, abbreviated to GDC) and CYA. GDC is a synthetic molecule presently in clinical cancer trials and has been reported to be safe and efficacious. These drugs attenuated early liver fibrosis in common bile duct ligated rats, improved liver function, and prevented hepatic stellate cell (HSC) activation, thereby suppressing epithelial to mesenchymal transition (EMT). While both CYA and GDC increased the number of proliferating cell nuclear antigen positive liver cells in vivo, only CYA increased Caspase-3 expression in HSCs in rat livers, suggesting that while GDC and CYA effectively attenuate early liver fibrosis, their hepatoprotective effects may be mediated through different modes of action. Thus, GDC has the potential to serve as a new therapeutic agent for treating early liver fibrosis.

The half-life of vismodegib after a single dose is 12 days, and after continuous daily dosing is 4 days.

The estimated elimination half-life of vismodegib is 4 days after continuous once-daily dosing and 12 days after a single dose.

Vismodegib is mainly metabolized by CYP2C9 and CYP3A4 in the liver; however, more than 98% of total systemic vismodegib is not metabolized. 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.

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.

2-Chloro-N-(4-chloro-3-(pyridin-2-yl)-phenyl)-4-(methylsulfonyl)-benzamide (GDC-0449, vismodegib) is a potent and selective first-in-class small-molecule inhibitor of the Hedgehog signaling pathway and is currently in clinical development. In this study, we investigated the metabolic fate and disposition of GDC-0449 in rats and dogs after a single oral administration of (14)C-GDC-0449. ... GDC-0449 underwent extensive metabolism in rats and dogs with the major metabolic pathways being oxidation of the 4-chloro-3-(pyridin-2-yl)-phenyl moiety followed by phase II glucuronidation or sulfation. Three other metabolites resulting from an uncommon pyridine ring opening were found, mainly in feces, representing 1.7 to 17.7% of the dose in total in rats and dogs. ...

... Proposed metabolites from exploratory metabolite identification in vitro (rat, dog and human liver microsomes) and in vivo (dog and rat urine) include three primary oxidative metabolites (M1-M3) and three sequential glucuronides (M4-M6). Oxidative metabolites identified in microsomes M1 and M3 were formed primarily by P4503A4/5 (M1) and P4502C9 (M3). GDC-0449 was not a potent inhibitor of P4501A2, P4502B6, P4502D6, and P4503A4/5 with IC50 estimates greater than 20 uM. K(i)'s estimated for P4502C8, P4502C9 and P4502C19 and were 6.0, 5.4 and 24 uM, respectively. An evaluation with Simcyp suggests that GDC-0449 has a low potential of inhibiting P4502C8 and P4502C9. Furthermore, GDC-0449 (15 uM) was not a potent P-glycoprotein/ABCB1 inhibitor in MDR1-MDCK cells.

25X868M3DS

VISMODEGIB

Established Pharmacologic Class [EPC] - Hedgehog Pathway Inhibitor

Mechanisms of Action [MoA] - Smoothened Receptor Antagonists

Vismodegib is a Hedgehog Pathway Inhibitor. The mechanism of action of vismodegib is as a Smoothened Receptor Antagonist.

VISMODEGIB

Vismodegib appears to have a nonlinear pharmacokinetic profile following daily oral dosing, and steady state is achieved within 7 days. A dose increase from 150 mg to 540 mg (1 to 3.6 times the recommended dose) does not lead to an increase in steady-state plasma concentrations. With a once-daily dose of 150 mg, the average plasma concentration of vismodegib at steady state is approximately 23 µM. The absolute bioavailability of a single dose of vismodegib is 31.8%. Absorption is saturable and is not affected by food.

Vismodegib is excreted mostly unchanged. Vismodegib and its metabolites are mainly eliminated through feces. Approximately 82% and 4.4% of the administered dose are recovered in feces and urine, respectively.

The volume of distribution of vismodegib ranges between 16.4 and 26.6 L.

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.

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.

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.

MEDICATION

Antineoplastic