Vismodegib

Mechanism of Action

The Hedgehog pathway regulates cell growth and differentiation in embryogenesis. This pathway is not active in adult tissue. PTCH1 is a tumor suppressor gene involved in the SHH pathway. SMO is a G-protein-coupled transmembrane receptor involved in signal transduction of the SHH pathway. Mutations in the smoothened (SMO) and PTCH1 genes appear to lead to abnormal up-regulation and activation of the SHH signaling pathway. Protein patched homolog 1 (Patched) is produced by the gene PTCH1 and functions as a transmembrane receptor that, when activated, suppresses the migration of the SMO receptor to the cell membrane. When the SHH ligand binds to Patched, the SMO receptor is released into the cell membrane, after which activation of cell proliferation occurs. In basal cell carcinoma, mutations in the Hedgehog pathway can result in an unrestricted proliferation of basal cells; researchers have noted that this pathway is relevant in more than 90% of basal cell carcinoma cases. One of the mechanisms believed to be involved in tumorigenesis involves ligand-independent pathway activation by SMO.

Vismodegib is a selective Hedgehog pathway inhibitor that binds to and competitively inhibits SMO. Inhibition of SMO results in transcription factors GLI1 and GLI2 remaining inactive; this prevents the expression of tumor-mediating genes within the Hedgehog pathway.[6][7][8]

Mutations in PTCH1 have correlations with nevoid basal cell carcinoma syndrome (Gorlin syndrome), trichoepitheliomas, squamous cell carcinoma of the esophagus, transitional cell carcinoma of the bladder, and holoprosencephaly. Medulloblastoma is a nervous system tumor associated with Hedgehog pathway mutations in as much as 30% of cases.

Pharmacokinetics/Pharmacodynamics

Vismodegib has a bioavailability of approximately 32% and has time-to-peak levels of approximately 2.4 days. Greater than 98% of the drug circulates as the original compound. Once absorbed, it has a volume of distribution (Vd) between 16 and 26.6 liters and is highly protein-bound (greater than 99%) to serum albumin and alpha acid glycoprotein (AAG). Vismodegib undergoes metabolism by oxidation, glucuronidation, and ring cleavage. It is a minor substrate for CYP2C9 and CYP3A4. The half-life of elimination after a single dose is approximately 12 days, but with continuous daily dosing, it becomes four days before it is eliminated primarily in the feces (82%) and urine (4%).

It is also noteworthy that vismodegib concentrates in the semen of men.

Administration

Vismodegib is available as a 150-mg oral-use capsule. It is dosed at 150-mg orally once daily until disease progression or unacceptable toxicity. 

However, adverse effects associated with vismodegib may serve as a barrier to lifelong treatment. Recently in an article published in Lancet Oncology, intermittent dosing protocols were examined over 73 weeks, comparing two groups with different dosing, Group A and Group B.  Group A received 12 weeks of vismodegib followed by eight weeks of placebo, which was repeated until the 73-week mark. Group B was given vismodegib initially for 24 weeks, followed by eight weeks of placebo, and then alternating eight weeks of vismodegib with eight weeks of placebo until the 73-week mark.

Both groups A and B showed a reduction in the mean number of basal cell carcinoma lesions from baseline (62.7% and 54%, respectively). However, the number of treatment-emergent events was higher in group B. Treatment activity and adherence were also lower within group B when compared to group A. It is likely that researchers will examine different dosing protocols going forward to balance adverse effects with treatment effectiveness.

Adverse Effects

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 most common adverse effects include muscle spasm (72%), fatigue (40%), alopecia (64%), dysgeusia (55%), and weight loss (45%). Other adverse effects associated with vismodegib include nausea, diarrhea, constipation, decreased appetite, ageusia, and arthralgias. Some patients may experience electrolyte disturbances, including hypokalemia or hyponatremia. Additionally, there may be elevated creatine phosphokinase levels and azotemia.

Recently, researchers at the University of California in San Francisco evaluated vismodegib to see if there was a risk of developing subsequent squamous cell carcinoma following use. A retrospective cohort study determined that vismodegib was not associated with an increased risk of SCC compared to those with standard surgical treatment for basal cell carcinoma. However, further studies are likely to examine this topic.

Contraindications

Vismodegib is contraindicated in pregnant women or women who may become pregnant.

Boxed Warning of Embryofetal Toxicity 

Embryotoxic effects include:

• Craniofacial abnormalities
• Anorectal defects
• Fused or absent digits

Blood Donations

Patients should be advised not to donate blood or blood products during vismodegib treatment and at least 24 months after the last dose.

Important Special Warnings

Counseling of both males and females on vismodegib is necessary.

Women

Following a negative pregnancy test, initiate highly effective contraception before the first dose of vismodegib and continue for seven months after treatment.

Men

During treatment, and for three months following treatment, men should not donate sperm and should use condoms with spermicide (even after vasectomy) as vismodegib may be present in seminal fluid. This precaution is to avoid exposure to patients that may be pregnant.

Monitoring

Pregnancy test within one week before treatment initiation.

Enhancing Healthcare Team Outcomes

The prescription of vismodegib is limited to the oncologist and dermatologist. However, the pharmacist also needs to know the basic principles of this agent. Oncology-trained specialty nurses also need to understand the basic mechanism and administration of the drug. Therefore, interprofessional coordination and information sharing need to be the norm in vismodegib therapy to improve outcomes and reduce potential adverse effects. [Level 5]

Initially approved in 2012, vismodegib is the first FDA-approved pharmacologic agent that targets the Hedgehog signaling pathway (sonic hedgehog, SHH), a pathway involved in many basal cell carcinomas. Not all patients are suitable candidates for surgery or topical therapy due to locally advanced or metastatic basal cell carcinoma; this is when vismodegib has a place in treatment.

The adverse effects of vismodegib have been a limiting factor for the medication. The most common adverse effects include muscle spasm (72%), fatigue (40%), alopecia (64%), dysgeusia (55%), and weight loss (45%). There is renewed concern that the drug may induce the development of squamous cell cancer. Hence, all patients prescribed vismodegib require close surveillance.[9][10]