hedgehog ( IC50 = 3 nM ); P-gp ( IC50 = 3.0 μM ); ABCG2 ( IC50 = 1.4 μM )

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]

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.

MDCKII cells are allowed to adhere after being seeded at a density of 3 × 10⁵ 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 Ca²⁺ and Mg²⁺, 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.

Mice:
Mice bearing tumors are grouped into cohorts based on tumor volume when the tumors grow to a size of 200–350 mm³. 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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Rats:
Vismodegib (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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Preclinical 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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Based 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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Absorption, Distribution and Excretion
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.
While recent publications have suggested the pharmacokinetics (PK) of vismodegib appear to be non-linear, there has not been a report describing the mechanisms of non-linearity. This study provides evidence that two separate processes, namely, solubility-limited absorption and concentration-dependent plasma protein binding, can explain the non-linear PK of vismodegib. This study provides quantitative results which can account for the lower than expected accumulation of vismodegib with continuous daily dosing. Vismodegib has demonstrated clinical activity in patients with advanced basal cell carcinoma. The pharmacokinetics (PK) of vismodegib are non-linear. The objective of this study was to determine whether vismodegib PK change following repeated dosing by administering a tracer intravenous (iv) dose of (14) C-vismodegib with single and multiple oral doses. Healthy post menopausal female subjects (n= 6/group) received either a single or daily 150 mg vismodegib oral dose with a (14) C-labelled 10 ug iv bolus dose administered 2 hr after the single or last oral dose (day 7). Plasma samples were assayed for vismodegib by LC-MS/MS and for (14) C-vismodegib by accelerator mass spectrometry. Following a single i.v. dose, mean clearance, volume of distribution and absolute bioavailability were 43.4 mL hr(-1) , 16.4 l and 31.8%, respectively. Parallel concentration-time profiles following single oral and i.v. administration of vismodegib indicated elimination rate limited PK. Following iv administration at steady-state, mean clearance and volume of distribution were 78.5 mL hr(-1) and 26.8 L, respectively. Comparison of iv PK parameters after single and multiple oral dosing showed similar half-life, increased clearance and volume of distribution (81% and 63% higher, respectively) and decreased bioavailability (77% lower) after repeated dosing. Relative to single dose, the unbound fraction of vismodegib increased 2.4-fold with continuous daily dosing. Vismodegib exhibited a long terminal half-life after oral and iv administration, moderate absolute bioavailability and non-linear PK after repeated dosing. Results from this study suggest that the non-linear PK of vismodegib result from two separate, non-linear processes, namely solubility limited absorption and high affinity, saturable plasma protein binding.
For more Absorption, Distribution and Excretion (Complete) data for Vismodegib (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
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.

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Biological Half-Life
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.

Hepatotoxicity
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 hepatotoxicity. However, a subsequent review of all published studies of vismodegib mentions that liver enzyme elevations occurred 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. In one 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. Thus, clinically apparent liver injury from vismodegib occurs, but is somewhat rare.
Likelihood score: C (probable cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of vismodegib during breastfeeding. Because vismodegib is more than 99% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life is 4 days and it might accumulate in the infant. The manufacturer recommends that breastfeeding be discontinued during vismodegib therapy and for 24 months after the final dose.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Vismodegib has high plasma protein binding (>99%). Vismodegib binds to plasma albumin and alpha-1-acid glycoprotein (saturable binding).

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Interactions
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.

[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 capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. /Included in US product label/

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Drug Warnings
/BOXED WARNING/ WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS ERIVEDGE (vismodegib) capsule can result in embryo-fetal death or severe birth defects. Erivedge is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations. Verify pregnancy status prior to the initiation of Erivedge. Advise male and female patients of these risks. Advise female patients of the need for contraception and advise male patients of the potential risk of Erivedge exposure through semen.
Advise patients not to donate blood or blood products while receiving Erivedge and for at least 7 months after the last dose of Erivedge.
Dysregulated hedgehog signaling is the pivotal molecular abnormality underlying basal-cell carcinomas. Vismodegib is a new orally administered hedgehog-pathway inhibitor that produces objective responses in locally advanced and metastatic basal-cell carcinomas. /The researchers/ tested the anti-basal-cell carcinoma efficacy of vismodegib in a randomized, double-blind, placebo-controlled trial in patients with the basal-cell nevus syndrome at three clinical centers from September 2009 through January 2011. The primary end point was reduction in the incidence of new basal-cell carcinomas that were eligible for surgical resection (surgically eligible) with vismodegib versus placebo after 3 months; secondary end points included reduction in the size of existing basal-cell carcinomas. In 41 patients followed for a mean of 8 months (range, 1 to 15) after enrollment, the per-patient rate of new surgically eligible basal-cell carcinomas was lower with vismodegib than with placebo (2 vs. 29 cases per group per year, P<0.001), as was the size (percent change from baseline in the sum of the longest diameter) of existing clinically significant basal-cell carcinomas (-65% vs. -11%, P=0.003). In some patients, all basal-cell carcinomas clinically regressed. No tumors progressed during treatment with vismodegib. Patients receiving vismodegib routinely had grade 1 or 2 adverse events of loss of taste, muscle cramps, hair loss, and weight loss. Overall, 54% of patients (14 of 26) receiving vismodegib discontinued drug treatment owing to adverse events. At 1 month, vismodegib use had reduced the hedgehog target-gene expression by basal-cell carcinoma by 90% (P<0.001) and diminished tumor-cell proliferation, but apoptosis was not affected. No residual basal-cell carcinoma was detectable in 83% of biopsy samples taken from sites of clinically regressed basal-cell carcinomas. Vismodegib reduces the basal-cell carcinoma tumor burden and blocks growth of new basal-cell carcinomas in patients with the basal-cell nevus syndrome. The adverse events associated with treatment led to discontinuation in over half of treated patients. Comment in The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version. Destroy user interface controlVismodegib in advanced basal-cell carcinoma.
FDA Pregnancy Risk Category: D /POSITIVE EVIDENCE OF RISK. Studies in humans, or investigational or post-marketing data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective./
For more Drug Warnings (Complete) data for Vismodegib (8 total), please visit the HSDB record page.

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Pharmacodynamics
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.

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.)