Approved Drug: Vismodegib (Erivedge)
Treatment of adults with metastatic basal cell carcinoma, or locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation.
Mechanism of Action
Vismodegib is a Hedgehog pathway inhibitor. The Hedgehog pathway is essential to fetal development, but signaling is tightly controlled after the fetus is developed. In basal cell carcinoma, it appears that the pathway is reactivated, leading to malignant progression. Vismodegib binds to and inhibits Smoothened, a transmembrane protein involved in the Hedgehog signal transduction.
Vismodegib is highly permeable but not very soluble in liquids. Bioavailability of a single dose is 31.8%. More than 98% of the circulating drug components are parent drug, and the drug is highly protein-bound to plasma proteins (> 99%). Drug absorption is not influenced by food intake. Drug is primarily excreted as unchanged drug, but minor metabolites are produced by CYP enzymes. Drug is a substrate of CYP2C9 and CYP3A4 pathways, but drug appears unaffected by concurrent administration of CYP3A4 inducers or inhibitors. Drug and its metabolites are primarily eliminated by the liver, with 82% of drug recovered in the feces, and 4.4% recovered in the urine. Elimination half-life is about 4 days after continuous dosing, and 12 days after a single dose. Patient age, weight, creatinine clearance (30–80 mL/min), and sex do not effect drug exposure. Drug has not been studied in patients with hepatic or renal impairment.
Oral, 150 mg taken once daily with or without food, for as long as patient derives clinical benefit. Swallow whole. If a dose is forgotten, resume dosing with next scheduled dose.
• Available in 150-mg capsules, in a bottle containing 28 capsules. Bottle should be stored at room temperature.
• Within 7 days prior to starting therapy, verify that female patients are not pregnant as drug can cause embryo-fetal death and severe birth defects.
• Drug should not be used by nursing mothers.
• Vismodegib capsules should be taken whole once daily. Do not crush the capsules, and do not make up a skipped dose. The next dose should be taken as scheduled.
• Patients should NOT donate blood or blood products while taking vismodegib, or for 7 months after the last drug dose.
• Women of childbearing age who are sexually active should use highly effective contraception during and for 7 months following the last dose of drug.
• Women of childbearing age who have unprotected sex, think that their birth control has failed, or think that they are pregnant need to talk to their providers right away.
• Men who are sexually active with female partners should use a condom with spermicide during treatment and for 2 months after the last dose, even if they have had a vasectomy, as drug may be present in semen.
• Men need to notify their healthcare providers right away if their partners may have become pregnant.
• P-glycoprotein (P-gp) inhibitors (eg, clarithromycin, erythromycin, azithromycin): may increase vismodegib serum levels with increased risk of adverse events.
• Drugs that alter gastric pH (eg, proton pump inhibitors, H2-receptor antagonists, antacids): may reduce vismodegib bioavailability and drug effectiveness.
• Healthcare providers should counsel patients on pregnancy prevention, and report to Genentech any cases of exposure during pregnancy (directly in female patients, or via seminal fluid from male patients). Healthcare providers should encourage pregnant patients to participate in Genentech’s Erivedge pregnancy pharmacovigilance program, which collects information about exposure during pregnancy, and the effects on the mother and unborn child. (More information is available by calling 1-888-835-2555.)
• Drug is FDA approved based on a single-arm, multicenter, open-label two-cohort trial of 104 patients with a median age of 62 years. All patients were white. Median duration of treatment was 10.2 months. Overall response rates were 30.3% in patients with metastatic basal cell carcinoma, and 42.9% in patients with locally advanced disease. Among those with locally advanced disease, 20.6% of responding patients had a complete response. Median response duration was 7.6 months for each group.
• No contraindications
• Drug is potentially embryo toxic (fetal death) and likely causes severe birth defects. Pregnancy should be avoided.
Adverse Reactions to Vismodegib by Body System
(boldface type indicates more common events, with 25% or higher incidence)
GI: Nausea, diarrhea, weight loss, decreased appetite, dysgeusia, constipation, vomiting
Musculoskeletal: Muscle spasm, arthralgias
Reproductive: Embryo-fetal death, severe birth defects, skipped periods in premenopausal women
Laboratory: Hyponatremia, hypokalemia, azotemia
Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Wilkes GM: Targeted Anti-Cancer Therapy: A Nursing Guide. Sudbury, MA, Jones and Bartlett Publishers, 2010.
2. Paladini RD, Saleh J, Qian C, et al: Modulation of hair growth with small molecule agonists of the Hedgehog signaling pathway. J Invest Dermatol 125(4):638–646, 2005.
3. BioOncology.com, Genentech, Inc: Hedgehog Research and Pathway Signaling. Available at http://www.biooncology.com/research-education/hedgehog/index.html. Accessed on July 23, 2012.
4. Lee SW, Moskowitz MA, Sims JR: Sonic hedgehog inversely regulates the expression of angiopoietin-1 and angiopoietin-2 in fibroblasts. Int J Mol Med 19(3):445–451, 2007.
5. Bailey JM, Mohr AM, Hollinsworth MA: Sonic hedgehog paracrine signaling regulates metastases and lymphangiogenesis in pancreatic cancer. Oncogene 28(4):3513–3525, 2009.
6. Adolphe C, Hetherington R, Ellis T, et al: Patched 1 functions as a gatekeeper by promoting cell cycle progression. Cancer Res 66:2081–2088, 2006.
7. Epstein EH: Basal cell carcinomas: Attack of the hedgehog. Nat Rev Cancer 8(10):743–754, 2008.
8. Dimou A, Syrigos K, Saif MW: Rationale for inhibition of the hedgehog pathway paracrine loop in pancreatic adenocarcinomas. JOP 12(1):1–5, 2011.