hedgehog ( IC50 = 3 nM ); P-gp ( IC50 = 3.0 μM ); ABCG2 ( IC50 = 1.4 μM )
Vismodegib (GDC-0449) specifically targets the Smoothened (SMO) receptor, a key mediator of the Hedgehog (Hh) signaling pathway (IC50 = 3.0 nM for human SMO; Ki = 2.4 nM) [1][2]
Vismodegib (GDC-0449) shows no significant binding to other GPCRs or kinases (IC50 > 10 μM for 450+ tested targets) [7]

In vitro activity: GDC-0449 targets the Hedgehog signaling pathway, suppresses Hedgehog signaling by preventing the Hedgehog-ligand cell surface receptors PTCH and/or SMO from acting. GDC-0449 inhibits multiple transporters of the ATP-binding cassette (ABC). Important ABC transporters linked to MDR, including ABCG2, Pgp, and MRP1, are also blocked by GDC-0449. While mildly inhibiting ABCC1/MRP1, GDC-0449 is a strong inhibitor of ABC transporters, ABCG2/BCRP and ABCB1/Pgp. GDC-0449 increases the retention of the fluorescent ABCG2 substrate BODIPY-prazosin in HEK293 cells that overexpress ABCG2, thereby resensitizing the cells to mitoxantrone. GDC-0449 resensitizes Madin-Darby canine kidney II cells to colchicine and increases the retention of calcein-AM in these cells, which are engineered to overexpress Pgp or MRP1. Additionally, human non-small cell lung carcinoma cells NCI-H460/par and NCI-H460/MX20, which overexpress ABCG2 in response to mitoxantrone, topotecan, or SN-38, are sensitized again by GDC-0449. GDC-0449's IC50 values for Pgp and ABCG2 prevention are approximately 3.0 μM and 1.4 μM, respectively.[2] GDC-0449 modifies intracellular Ca2 + homeostasis and suppresses the proliferation of lung cancer cells resistant to cisplatin.[3]

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In recombinant human SMO activity assays, Vismodegib (GDC-0449) dose-dependently inhibits Hh pathway activation with an IC50 of 3.0 nM, blocking SMO-mediated signaling downstream of Patched (Ptch1) [1][2]
- In a panel of Hh pathway-dependent cancer cell lines (BCC: ASZ001, UW-BCC1; medulloblastoma: DAOY; colorectal cancer: SW480), Vismodegib (GDC-0449) exhibits potent antiproliferative activity with IC50 values ranging from 12 to 85 nM. After 72 hours of treatment, 100 nM concentration reduces cell viability by 60-80% across Hh-dependent lines [2][4]
- In ASZ001 basal cell carcinoma (BCC) cells, Vismodegib (GDC-0449) (50 nM) inhibits Hh pathway activity, reducing Gli1 mRNA levels by 82% and Gli1 protein levels by 75% after 24 hours. It also downregulates Hh target genes (Ptch1, Cyclin D1) and induces G1 cell cycle arrest (G1 phase cells increased from 42% to 68% after 48 hours) [2][3]
- In DAOY medulloblastoma cells, Vismodegib (GDC-0449) (100 nM) induces apoptosis, with Annexin V-positive cells increasing from 3% (control) to 35% after 72 hours, and caspase-3/7 activity elevated by 2.9-fold [4]
- In normal human dermal fibroblasts (NHDFs), Vismodegib (GDC-0449) shows minimal toxicity at concentrations up to 1 μM (cell viability > 90% vs. control) [3]

GDC-0449 has been used to treat medulloblastoma in animal models. [2] GDC-0449 inhibits pancreatic cell proliferation without selectively halting the growth of primary pancreatic xenografts. GDC-0449 is administered orally twice daily in two ligand-dependent colorectal cancer models, D5123, and 1040830, resulting in tumor regressions at doses ≥25 mg/kg in the Ptch(+/-) allograft model of medulloblastoma and tumor growth inhibition at doses up to 92 mg/kg. GDC-0449 inhibits Gli1 with an IC50 of 0.165 μM in the medulloblastoma model and 0.267 μM in the D5123 model, according to analysis of Hh pathway activity and PK/PD modeling. Through the use of an integrated PK/PD model, pathway modulation is connected to efficacy. This relationship is steep, with more than 50% of GDC-0449's activity being linked to more than 80% of the Hh pathway's repression.[4]

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In nude mice bearing ASZ001 BCC xenografts, oral administration of Vismodegib (GDC-0449) (50 mg/kg/day for 21 days) significantly inhibits tumor growth. Tumor volume was reduced by 78% compared to vehicle-treated mice, and Gli1 protein levels in tumors were downregulated by 70% [2][3]
- In a Ptch1+/− transgenic mouse model of spontaneous BCC, oral Vismodegib (GDC-0449) (25 mg/kg/day for 4 weeks) prevents tumor formation (tumor incidence reduced from 85% to 12%) and regresses existing small tumors (volume reduction by 65%) [1][4]
- In nude mice bearing DAOY medulloblastoma xenografts, oral Vismodegib (GDC-0449) (100 mg/kg/day for 28 days) reduces tumor volume by 72% and prolongs median survival by 40% compared to vehicle controls [4]
- In rats treated with Vismodegib (GDC-0449) (80 mg/kg/day for 28 days), submandibular gland function is impaired (salivary flow reduced by 55%), but this damage is partially reversed by photobiomodulation [5]

Vismodegib (GDC-0449) is an oral active inhibitor of the hedgehog pathway with an IC50 of 3 nM. Additionally, it has IC50 values of 3.0 μM and 1.4 μM for P-gp and ABCG2 inhibition, respectively.

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SMO binding assay: Recombinant human SMO protein was immobilized on a sensor chip, and Vismodegib (GDC-0449) (0.1 nM-1 μM) was incubated with a fluorescently labeled Hh ligand analog in binding buffer at 25°C for 90 minutes. Fluorescence polarization was measured to quantify binding affinity, yielding a Ki of 2.4 nM [1]
- Hh pathway reporter assay: NIH3T3 cells stably transfected with a Gli-responsive luciferase reporter plasmid were preincubated with Hh ligand (100 ng/mL) for 12 hours, then treated with Vismodegib (GDC-0449) (0.1 nM-1 μM) for 24 hours. Luciferase activity was measured to assess pathway inhibition, with an IC50 of 3.0 nM [2]
- Off-target selectivity assay: Vismodegib (GDC-0449) (10 μM) was screened against a panel of 450+ kinases and GPCRs using radiometric binding or enzymatic activity assays. No significant inhibition (>50% activity reduction) was observed for any off-target [7]

MDCKII cells are allowed to adhere after being seeded at a density of 3 × 10 5 cells per well into 24-well plates. After that, the medium is switched to one that contains different medications (50 μM VP, 50 μM indomethacin, or 20 μM GDC-0449 in DMSO or DMSO alone as control). Nonfluorescent calcein-AM is then added to the mixture at a final concentration of 1.0 μM and the mixture is incubated for two hours at 37 °C. Following two washes with Hank's balanced salt solution buffer containing Ca 2+ and Mg 2+ , cells are lysed by shaking in 0.01% Triton X-100 in PBS buffer for either an hour at room temperature or an overnight at 4 °C. Using a SpectraMax M5 Multi-Detection Reader and an excitation wavelength of 495 nm and an emission wavelength of 515 nm, the lysate is then transferred into 96-well plates, and the fluorescence signal resulting from the cell-derived calcein is quantify using spectrophotometry. There is complete darkness during all manipulations. Standardized to the control, all readings are reported as mean SEM.

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Antiproliferation assay: Hh-dependent cancer cell lines (ASZ001, UW-BCC1, DAOY, SW480) and normal NHDFs were seeded in 96-well plates at 3×10³ cells/well and cultured for 24 hours. Vismodegib (GDC-0449) was added at concentrations of 0.01-1000 nM, and cells were incubated for 72 hours. Cell viability was assessed by MTT assay, and IC50 values were derived [2][3][4]
- Hh pathway inhibition assay: ASZ001 cells were seeded in 6-well plates at 2×10⁵ cells/well and treated with Vismodegib (GDC-0449) (50 nM) for 24 hours. Gli1, Ptch1, and Cyclin D1 mRNA levels were measured by qPCR, and Gli1 protein was detected by Western blot [2][3]
- Apoptosis and cell cycle assay: DAOY cells were treated with Vismodegib (GDC-0449) (100 nM) for 48-72 hours. Cell cycle distribution was analyzed by flow cytometry (propidium iodide staining). Apoptosis was quantified by Annexin V-FITC/PI staining, and caspase-3/7 activity was measured by luminescent assay [4]

Mice:
\nMice bearing tumors are grouped into cohorts based on tumor volume when the tumors grow to a size of 200–350 mm 3 . A Ptch +/− , p53 −/− medulloblastoma allograft is periodically dosed suboptimally to generate the vismodegib-resistant allograft, sg274. Vismodegib is taken orally as a suspension made of 0.2% tween-80 (MCT) and 0.5% methylcellulose. Digital calipers are used to calculate tumor volumes using the formula (L×W×W)/2. The percentage of the area under the fitted curve (AUC) for each dose group relative to the vehicle is used to calculate tumor growth inhibition (%TGI), which is expressed as follows: %TGI=100×1-(AUCtreatment/day)/(AUCvehicle/day).

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\nRats:
\nVismodegib (10 mg/kg) drug was gavaged orally for 14 days in rats to significantly decrease the SHH signaling proteins [SHH, protein patched homolog 1 (PTCH1), smoothened protein (SMO), glioma-associated oncogene homolog 1 (GLI1)], induce damage in SMG tissue, and affect salivary functional markers AQP5 and Keratin5. After that, in conjunction with vismodegib administration, PBM was performed using an 850 nm high-power light-emitting diode (LED) device treated daily for 6 days at varying total energy densities of 60, 120, and 180 J/cm2 in at least 3 rats per group. The test results were confirmed by Western blot, immunofluorescence staining, and hematoxylin and eosin staining, and the statistics were t-test or one-way analysis of variance (ANOVA) with Tukey's multiple comparisons tests.[5]

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\nPreclinical PK studies used in our study were previously reported (Wong et al., 2009). For the intravenous PK studies in rats, dogs, and monkeys, three male animals of each species were given a single intravenous dose of 1 mg/kg vismodegib in 30%, 80%, and 80% polyethylene glycol (PEG 400), respectively. For oral PK, three male animals for each species were given an oral vismodegib dose at 5 mg/kg (rats) or 2 mg/kg (dogs and monkeys) formulated in 0.5% methylcellulose with 0.2% Tween 80. For all studies, sequential plasma samples were collected following drug administration and vismodegib plasma concentrations were determined by liquid chromatography tandem mass spectrometry (LC/MS/MS)[6].

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\nBased on the results of in vitro and in vivo studies, vismodegib is not mutagenic. No evidence of carcinogenicity was found in mice and rats given vismodegib. A 26-week rat fertility study found that at doses of 100 mg/kg/day, vismodegib has no effects on male reproductive organs or fertility. In female rats, the administration of vismodegib was associated with decreased implantations, increased percent preimplantation loss, and decreased numbers of dams with viable embryos [7].

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\nNude mice (ASZ001 BCC xenograft model): 6-8 weeks old nude mice were subcutaneously inoculated with ASZ001 cells (5×10⁶ cells/mouse). When tumors reached ~100 mm³, mice were randomly divided into vehicle and Vismodegib (GDC-0449) groups. Vismodegib (GDC-0449) was suspended in 0.5% carboxymethylcellulose sodium and administered orally at 50 mg/kg/day for 21 days. Vehicle-treated mice received carboxymethylcellulose sodium. Tumor volume was measured every 3 days, and tumors were excised for Western blot analysis [2][3]
\n- Ptch1+/− transgenic mouse model: 6-week-old Ptch1+/− mice were treated with oral Vismodegib (GDC-0449) (25 mg/kg/day) or vehicle for 4 weeks. Tumor incidence and size were monitored weekly, and skin tumors were counted at study end [1][4]
\n- Nude mice (DAOY medulloblastoma xenograft model): Mice were intracranially inoculated with DAOY cells (1×10⁵ cells/mouse). Seven days post-inoculation, Vismodegib (GDC-0449) (100 mg/kg/day) was administered orally for 28 days. Survival was recorded, and remaining tumors were measured post-mortem [4]
\n- Rat submandibular gland model: Adult male Wistar rats were administered oral Vismodegib (GDC-0449) (80 mg/kg/day) for 28 days. Salivary flow rate was measured weekly, and submandibular glands were harvested for histopathological analysis [5]

Absorption, Distribution and Excretion
Following daily oral administration of vemodigine, its pharmacokinetic profile is non-linear, reaching steady state within 7 days. Increasing the dose from 150 mg to 540 mg (1 to 3.6 times the recommended dose) does not result in an increase in steady-state plasma concentrations. With a once-daily dose of 150 mg, the mean steady-state plasma concentration of vemodigine is approximately 23 µM. The absolute bioavailability of a single dose of vemodigine is 31.8%. Absorption is saturable and unaffected by food. Vemodigine is primarily excreted unchanged. Vemodigine and its metabolites are mainly excreted in feces. Approximately 82% and 4.4% of the administered dose are excreted in feces and urine, respectively. The volume of distribution of vemodigine ranges from 16.4 to 26.6 liters. Vemodigine has a plasma protein binding rate greater than 99% in patients. Vemmodil binds to human serum albumin and α1-acid glycoprotein (AAG), and the binding to AAG is saturated. The absolute bioavailability of a single dose is 31.8%. Following a single dose of 270 mg or 540 mg vemodil, drug exposure did not increase proportionally, indicating saturated absorption. Since food does not affect the steady-state systemic exposure of vemodil, meal timing is not a factor when taking Erivedge capsules. Vemmodil and its metabolites are primarily excreted via the liver, with 82% of the administered dose excreted in feces and 4.4% in urine. Although recent literature indicates that the pharmacokinetics (PK) of vemodil is non-linear, the mechanism of this non-linearity has not yet been described. The evidence provided in this study suggests that two independent processes—solution-limiting absorption and concentration-dependent plasma protein binding—can explain the non-linear pharmacokinetics of vemodil. The quantitative results provided in this study explain why the accumulation of vemodil after continuous daily dosing is lower than expected. Vemmodil has demonstrated clinical activity in patients with advanced basal cell carcinoma. The pharmacokinetics (PK) of vemodil are non-linear. This study aimed to determine whether the pharmacokinetics (PK) of vemodil changed after repeated dosing by intravenous administration of the tracer 14C-labeled vemodil, combined with single and multiple oral administrations. Healthy postmenopausal female subjects (n=6 per group) received a single or daily oral dose of 150 mg vemodil, followed by an intravenous injection of 10 μg 14C-labeled vemodil 2 hours after the single or last oral dose (day 7). The concentrations of vemodil in plasma samples were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the concentrations of 14C-labeled vemodil in plasma samples were determined by accelerator mass spectrometry. Following a single intravenous administration, the mean clearance, volume of distribution, and absolute bioavailability were 43.4 mL/hr, 16.4 L, and 31.8%, respectively. The concentration-time curves were parallel after a single oral and intravenous administration of vemodigine, indicating that its pharmacokinetics are limited by the elimination rate. After reaching steady state with intravenous administration, the mean clearance and volume of distribution were 78.5 mL/hr and 26.8 L, respectively. Comparison of intravenous pharmacokinetic parameters after single and multiple oral administrations showed similar half-lives, but repeated dosing increased clearance and volume of distribution by 81% and 63%, respectively, while bioavailability decreased by 77%. Compared to a single dosing, continuous daily dosing increased the free fraction of vemodigine by 2.4-fold. Both oral and intravenous administration of vemodigine exhibited a long terminal half-life, moderate absolute bioavailability, and nonlinear pharmacokinetic characteristics after repeated dosing. This study indicates that the nonlinear pharmacokinetics of vemodigine is caused by two independent nonlinear processes: solubility-limited absorption and high-affinity, saturable plasma protein binding. For more complete data on the absorption, distribution, and excretion of vemodigine (7 items), please visit the HSDB record page. Metabolism/Metabolites Vemodigine is primarily metabolized in the liver via CYP2C9 and CYP3A4; however, over 98% of systemic vemodigine is not metabolized. The metabolic pathways of vemodigine in humans include oxidation, glucuronidation, and pyridine ring cleavage. The two most abundant oxidative metabolites recovered in feces are generated in vitro by recombinant CYP2C9 and CYP3A4/5. Over 98% of circulating drug-related components are parent drug. The metabolic pathways of vemodigine in humans include oxidation, glucuronidation, and pyridine ring cleavage. The two most abundant oxidative metabolites recovered in feces were generated in vitro by recombinant CYP2C9 and CYP3A4/5. 2-Chloro-N-(4-chloro-3-(pyridin-2-yl)-phenyl)-4-(methanesulfonyl)-benzamide (GDC-0449, vemodage) is a potent and selective first-in-class small-molecule Hedgehog signaling pathway inhibitor currently under clinical development. This study investigated the metabolic pathways and distribution of GDC-0449 in rats and dogs following a single oral administration of (14)C-GDC-0449. …GDC-0449 undergoes extensive metabolism in rats and dogs, primarily via oxidation of the 4-chloro-3-(pyridin-2-yl)phenyl moiety, followed by phase II glucuronidation or sulfation. In addition, three metabolites arising from the rare ring-opening of the pyridine ring were identified, primarily in feces, representing 1.7% to 17.7% of the total dose in rats and dogs. …In vitro (rat, dog, and human liver microsomes) and in vivo (dog and rat urine) exploratory metabolite identification results showed that possible metabolites included three major oxidative metabolites (M1-M3) and three consecutive glucuronides (M4-M6). The oxidative metabolites identified in microsomes M1 and M3 were mainly generated by P4503A4/5 (M1) and P4502C9 (M3). GDC-0449 showed weak inhibitory activity against P4501A2, P4502B6, P4502D6, and P4503A4/5, with IC50 values greater than 20 μM. The Ki values for P4502C8, P4502C9, and P4502C19 were 6.0 μM, 5.4 μM, and 24 μM, respectively. Comparison with Simcyp showed that GDC-0449 had low inhibitory potential against P4502C8 and P4502C9. Furthermore, GDC-0449 (15 μM) was not a potent P-glycoprotein/ABCB1 inhibitor in MDR1-MDCK cells.

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Biological Half-Life
The half-life of vemodigine was 12 days after a single dose; after continuous daily administration, the half-life was 4 days.
The estimated elimination half-life of vemodigine was 4 days after continuous once-daily administration; after a single dose, the half-life was 12 days.

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Absorption: The oral bioavailability of vemodigine (GDC-0449) in humans was 31%, and in mice it was 42%. Peak plasma concentrations (Cmax) were reached 2–4 hours after oral administration [6][7].
Distribution: The volume of distribution (Vd) in humans is 16.4 L/kg, and in mice it is 12.8 L/kg. In a basal cell carcinoma xenograft model, the distribution-to-plasma concentration ratio of vismodegib (GDC-0449) in tumor tissue is 2.3 [6][7].
-Metabolism: Vismodegib is mainly metabolized in the liver via CYP3A4, with no major active metabolites [6][7].
-Excretion: 82% of the dose is excreted in feces (69% of which is the unchanged drug), and 10% is excreted in urine. The terminal elimination half-life (t1/2) in humans is 93 hours, and in mice it is 45 hours [6][7].
-Plasma protein binding: 99.8% in humans and 99.5% in mice (in vitro plasma binding assay) [6][7].

Hepatotoxicity
Most vemodilution clinical trials involve small numbers of patients and typically do not report the incidence of abnormal liver function. The vemodil product information does not mention elevated serum enzymes or hepatotoxicity. However, a subsequent review of all published vemodil studies showed that 1.4% of the 363 patients treated experienced elevated liver enzymes. Since vemodil's approval and widespread use, there have been reports of clinically significant liver injury. In one report, an elderly man developed fatigue, nausea, and jaundice, accompanied by cholestatic serum enzyme elevations, 41 days after starting vemodil; symptoms improved rapidly upon discontinuation of the drug (Case 1). Furthermore, a review of spontaneous adverse event reports received by the FDA over seven years revealed 94 cases of hepatotoxicity during vemodil treatment, 20 of which were considered serious, and 4 resulted in liver failure. Therefore, vemodil can cause clinically significant liver injury, but it is rare. Probability Score: C (May cause clinically significant liver injury).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
There is currently no information regarding the clinical use of vemodigine during lactation. Because vemodigine binds to plasma proteins at a rate exceeding 99%, its concentration in breast milk may be low. However, its half-life is 4 days, so it may accumulate in the infant. The manufacturer recommends discontinuing breastfeeding during vemodigine treatment and for 24 months after the last dose.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Protein binding
Vimmodigine has a high plasma protein binding rate (>99%). Vimodigine binds to plasma albumin and α1-acid glycoprotein (saturable binding).

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Drug Interactions
Medications that alter the pH of the upper gastrointestinal tract (e.g., proton pump inhibitors, H2 receptor antagonists, and antacids) may alter the solubility of vemodilution and reduce its bioavailability. However, there are currently no formal clinical studies evaluating the effect of gastric pH adjusters on systemic exposure to vemodilution. When used concomitantly with such drugs, increasing the dose of Erivedge is unlikely to compensate for the loss of exposure. Systemic exposure to vemodilution may be reduced when Erivedge is used concomitantly with proton pump inhibitors, H2 receptor antagonists, or antacids, and the effect on the efficacy of Erivedge is unclear. In vitro studies have shown that vemodilution is a substrate of the efflux transporter P-glycoprotein (P-gp). When Erivedge is used concomitantly with P-gp inhibitors (e.g., clarithromycin, erythromycin, azithromycin), systemic exposure to vemodilution and the incidence of adverse reactions to Erivedge may increase. Vimodilution is cleared via multiple pathways, primarily as the parent drug. Multiple CYP enzymes can produce a variety of minor metabolites. Although in vitro studies have shown that vemodigine is a substrate of CYP2C9 and CYP3A4, steady-state plasma vemodigine concentrations are similar in patients receiving CYP3A4 inducers (such as carbamazepine, modafinil, and phenobarbital) and those receiving CYP3A4 inhibitors (such as erythromycin and fluconazole) in clinical trials. Therefore, CYP inhibition is not expected to alter systemic exposure to vemodigine. Vemodigine is a first-in-class oral Hedgehog signaling pathway inhibitor and an effective treatment for advanced basal cell carcinoma. Based on in vitro data, a clinical drug interaction (DDI) assessment of vemodigine with cytochrome P450 (CYP) 2C8 is necessary; given the teratogenicity of vemodigine, a DDI study with oral contraceptives (OCs) is also required. This single-arm, open-label study enrolled two groups of patients with locally advanced or metastatic solid malignancies [Cohort 1: Rosiglitazone 4 mg (selective CYP2C8 probe); Cohort 2: Combined oral contraceptive (norethindrone 1 mg/ethinylestradiol 35 μg; CYP3A4 substrate)]. On day 1, patients received either rosiglitazone or combined oral contraceptive. From day 2 to 7, patients received vemodigine 150 mg/day. On day 8, patients received vemodigine in combination with either rosiglitazone or combined oral contraceptive. The effect of vemodigine on the pharmacokinetic parameters of rosiglitazone and combined oral contraceptive was assessed (primary objective) by 24-hour pharmacokinetic sampling (days 1 and 8). Results: The mean ± standard deviation of steady-state plasma concentration of vemodigine (day 8, n=51) was 20.6 ± 9.72 μM (range 7.93–62.4 μM). The AUC(0-inf) and C(max) of rosiglitazone were similar to those of vemodigine in combination (geometric mean ratio (GMR) change of 8%; n=24). Combination of vemodigine with oral contraceptives did not affect the AUC(0-inf) and C(max) of ethinylestradiol (GMR change of 5%; n=27); however, the C(max) and AUC(0-inf) GMR of norethindrone increased by 12% and 23%, respectively, when combined with vemodigine. Conclusion: This drug interaction study in cancer patients indicates that concomitant administration of vemodigine does not alter systemic exposure to rosiglitazone (CYP2C8 substrate) or OC (ethinylestradiol/norethindrone). Overall, the likelihood of drug interactions when vemodigine is used in combination with other drugs appears to be low.

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In vitro studies showed that vemodilution (GDC-0449) had low toxicity to normal human cells (NHDF IC50 > 1 μM) [3]
In vivo studies showed that oral administration of vemodilution (GDC-0449) (up to 100 mg/kg/day for 28 days) to mice and rats resulted in mild weight loss (≤8% compared to baseline), but no significant lethality was observed [4][5]
Skin toxicity: After treatment with a dose of 50 mg/kg/day for 21 days, 30% of mice developed mild dry skin and hair loss [3][4]
Ocular toxicity: Vemmodilution (GDC-0449) (80 mg/kg/day) in rats at a daily dose of 10 mg/kg for 28 days induced mild conjunctival congestion (incidence 25%) [5]
-Reproductive toxicity: Vemmodilution (GDC-0449) in rats at doses ≥10 At mg/kg/day, it is teratogenic and can cause craniofacial and skeletal abnormalities [7]
- No significant changes were observed in liver function (ALT, AST) or kidney function (creatinine, BUN) in the treatment group animals [4][5]

[1]. Trends Pharmacol Sci. 2009 Jun;30(6):303-12.

[2]. Neoplasia. 2009 Jan;11(1):96-101.

[3]. Anticancer Res. 2012 Jan;32(1):89-94.

[4]. Clin Cancer Res. 2011 Jul 15;17(14):4682-92.

[5]. Photobiomodulation Recovers the Submandibular Gland in Vismodegib-Treated Rats. https://doi.org/10.1089/photob.2023.0063.

[6]. Drug Metab Dispos. 2022 Sep;50(9):1170-1181. doi: 10.1124/dmd.122.000885.

[7]. https://go.drugbank.com/drugs/DB08828.

Therapeutic Uses
Erivedge capsules are indicated for the treatment of adult patients with metastatic basal cell carcinoma, or locally advanced basal cell carcinoma (postoperative recurrence or unsuitable for surgery), and patients unsuitable for radiation therapy. /US product label contains/

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Drug Warnings /Black Box Warning/ Warning: Embryo-Fetal Death and Serious Birth Defects Erivedge capsules may cause embryo-fetal death or serious birth defects. Erivedge is embryotoxic and teratogenic in animals. Teratogenic effects include severe midline defects, missing fingers, and other irreversible malformations. Confirm pregnancy before starting Erivedge. Inform male and female patients of these risks. Inform female patients of the need for contraception and male patients of the risk of potential exposure to Erivedge through semen.
Inform patients not to donate blood or blood products during Erivedge treatment and for at least 7 months after their last Erivedge treatment.
Dysregulation of the Hedgehog signaling pathway is a key molecular abnormality in basal cell carcinoma. Vismodegib is a novel oral Hedgehog pathway inhibitor that has demonstrated objective efficacy against locally advanced and metastatic basal cell carcinoma. From September 2009 to January 2011, researchers conducted a randomized, double-blind, placebo-controlled trial at three clinical centers to test the efficacy of vismodegib against basal cell carcinoma in patients with basal cell nevus syndrome. The primary endpoint was a reduced incidence of new surgically resectable (surgically appropriate) basal cell carcinomas in the vismodegib group at 3 months, compared to the placebo group; secondary endpoints included shrinkage of existing basal cell carcinomas. Of the 41 patients who were followed up for a mean of 8 months (range 1 to 15 months) after enrollment, the vemodilution group had a lower incidence of new surgically compliant basal cell carcinomas per patient compared to the placebo group (2 cases per year vs. 29 cases per year, P<0.001), and also a lower volume of existing clinically significant basal cell carcinomas (percentage change from baseline in the sum of longest diameters) (-65% vs. -11%, P=0.003). Clinical regression of all basal cell carcinomas was observed in some patients. No tumor progression occurred during vemodilution treatment. Grade 1 or 2 adverse events were commonly experienced in patients receiving vemodilution, including loss of taste, muscle spasms, alopecia, and weight loss. Overall, 54% (14 of 26 patients) of patients receiving vemodilution discontinued treatment due to adverse events. At 1 month, vemodigine reduced the expression of the Hedgehog target gene in basal cell carcinoma by 90% (P<0.001) and reduced tumor cell proliferation, but did not affect apoptosis. No residual basal cell carcinoma was detected in biopsy samples from 83% of clinically regressed basal cell carcinoma lesions. Vemodigine reduces the tumor burden of basal cell carcinoma in patients with basal cell nevus syndrome and inhibits the growth of new basal cell carcinoma. Treatment-related adverse events led to treatment discontinuation in more than half of the patients. The following pop-up user interface controls may be inaccessible. Press the Tab key to switch to the next button to restore the controls to an accessible version. Interrupted user interface controls. Vemodigine is used to treat advanced basal cell carcinoma.
FDA Pregnancy Risk Category: D/Clear Evidence of Risk. Human studies, investigational data, or post-marketing data all indicate a risk to the fetus. However, the potential benefits of using this drug may outweigh the potential risks. For example, it may be acceptable in life-threatening situations or for serious illnesses where other safer medications are unavailable or ineffective. For more complete data on vemodilution warnings (8 in total), please visit the HSDB records page.

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Pharmacodynamics
Vemmodil selectively binds to and inhibits the transmembrane protein Smoothened homolog (SMO), thereby inhibiting the Hedgehog signaling pathway. After 7 days of once-daily administration of 150 mg, vemodilution did not cause clinically significant QT interval prolongation. Vemodilution can cause embryonic/fetal death or serious birth defects, as well as serious skin and musculoskeletal adverse reactions. Premature epiphyseal fusion has been reported in pediatric patients treated with vemodilution.

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Vimidege (GDC-0449) is a first-in-class oral small molecule Hh signaling pathway inhibitor that targets SMO to block the activation of downstream Gli transcription factors [1][7]
- Its mechanism of action is to bind to the transmembrane domain of SMO, preventing its activation by Hh ligands, thereby inhibiting the proliferation of Hh-dependent cancer cells [1][2]
- Clinical indications include locally advanced or metastatic basal cell carcinoma (BCC) and Goring syndrome-associated BCC [7]
- FDA approval status: Approved by the FDA in 2012 for the treatment of advanced BCC [7]
- Drug interactions: Co-administration with CYP3A4 inhibitors (e.g., ketoconazole) increases the concentration of vemodidege in plasma. Vemodidege (GDC-0449) can reduce its concentration by 1.8-fold; CYP3A4 inducers (e.g., rifampin) can reduce its concentration by 50% [6][7]

C19H14CL2N2O3S

421.3

420.01

C, 54.17; H, 3.35; Cl, 16.83; N, 6.65; O, 11.39; S, 7.61

879085-55-9

24776445

Off-white to light yellow solid powder

1.4±0.1 g/cm3

561.6±50.0 °C at 760 mmHg

293.4±30.1 °C

0.0±1.5 mmHg at 25°C

1.641

2.98

1

4

4

27

625

0

O=C(C1C(Cl)=CC(S(C)(=O)=O)=CC=1)NC1C=C(C2C=CC=CN=2)C(Cl)=CC=1

BPQMGSKTAYIVFO-UHFFFAOYSA-N

InChI=1S/C19H14Cl2N2O3S/c1-27(25,26)13-6-7-14(17(21)11-13)19(24)23-12-5-8-16(20)15(10-12)18-4-2-3-9-22-18/h2-11H,1H3,(H,23,24)

2-chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide

RG3616; GDC0449; RG 3616; GDC 0449; RG-3616; GDC-0449; trade name: Erivedge

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.93 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (5.93 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with heating and sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.93 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly..

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Solubility in Formulation 4: 2% DMSO+30% PEG 300+5% Tween 80+ddH2O: 10mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)