sonidegib

Action and Spectrum

Actions and Spectrum: 

sonidegib is a medication that belongs to a class of drugs called hedgehog pathway inhibitors. It is used to treat basal cell carcinoma, a type of skin cancer. The hedgehog pathway is involved in the development and growth of cells, and by inhibiting this pathway, sonidegib can help prevent the growth and spread of cancer cells. 

The spectrum of sonidegib refers to the range of organisms or diseases that the drug is effective against. In this case, sonidegib is only effective against basal cell carcinoma, and is not used to treat other types of cancer or diseases. 

As for its actions, sonidegib specifically targets the Smoothened protein, which is a key component of the hedgehog signaling pathway. By blocking Smoothened, sonidegib prevents the activation of the pathway and the expression of genes involved in cell growth and proliferation. This ultimately leads to the inhibition of tumor growth and the destruction of cancer cells in basal cell carcinoma. 

Drug Interaction

Adverse Reaction

Frequency defined:  

>10% 

Increased serum creatinine  

Increased serum creatine kinase  

Muscle spasms  

Alopecia  

Hyperglycemia  

Dysgeusia  

Increased lipase  

Fatigue  

Nausea 

Diarrhea  

Anemia  

Musculoskeletal pain  

Decreased weight  

Lymphopenia  

Decreased appetite  

Myalgia  

Increased ALT or AST  

Abdominal pain  

Increased amylase  

Headache 

Pain  

Vomiting  

1-10% 

 Increased serum creatine kinase  

Hyperglycemia  

Increased ALT/AST  

Muscle spasms 

Decreased weight  

Lymphopenia  

Decreased appetite  

Musculoskeletal pain  

Nausea  

Diarrhea  

Vomiting  

Increased amylase  

Black Box Warning

Black-Box Warning: 

sonidegib is a drug that inhibits the Hedgehog signaling pathway, which is involved in cell growth and differentiation. This pathway plays a critical role in embryonic development, and its disruption can lead to birth defects or fetal death. Therefore, based on the available data, sonidegib can cause embryo-fetal death or severe birth defects when administered to a pregnant woman.  

Animal studies have confirmed that sonidegib is embryotoxic, fetotoxic, and teratogenic, meaning it can harm the developing fetus and cause birth defects. To minimize the risk of harm to the fetus, it is recommended to verify the pregnancy status of females of reproductive potential before initiating treatment.

Females of reproductive potential should be advised to use effective contraception during treatment and for at least 20 months after the last dose to prevent pregnancy. Male patients should also be advised to use condoms, even after a vasectomy, to avoid potential drug exposure to pregnant partners and female partners of reproductive potential during treatment and for at least 8 months after the last dose. 

Contraindication / Caution

Contraindication/Caution: 

sonidegib is contraindicated in pregnant women and should not be used during pregnancy. It is also contraindicated in patients with a known hypersensitivity to the drug or any of its components.  

sonidegib should be used with caution in patients with a history of cardiac disease, as it can cause prolongation of the QT interval. It should also be used with caution in patients with hepatic impairment, as sonidegib is primarily metabolized in the liver. Dose adjustments may be required in these patients.  

sonidegib can also cause musculoskeletal adverse events such as muscle spasms, arthralgia, and myalgia. Patients should be advised to report any new or worsening symptoms promptly.  

Additionally, sonidegib can interact with certain medications that are metabolized by the CYP3A4 enzyme. Concomitant use of strong CYP3A4 inhibitors or inducers should be avoided, or dose adjustments may be necessary.  

Overall, sonidegib should be used with caution in patients with pre-existing medical conditions or who are taking medications that may interact with it. It is important to discuss any potential risks and benefits of using sonidegib with a healthcare provider before starting treatment

Pregnancy / Lactation

Pregnancy consideration: The drug is toxic and unsafe for pregnant women and the developing fetus.  

Breastfeeding warnings: No data on the excretion of sonidegib in breast milk is available. Because of possible serious effects, women are advised to breastfeed one week after the last dose of sonidegib. 

Pregnancy category: 

• Category A: Satisfactory and well-controlled studies show no risk to the fetus in the first or later trimester. 
• Category B: There is no affirmation of risk to the fetus found in animal reproduction studies, and there are not enough studies on pregnant women. 
• Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for a product in humans; Pregnant women must take care of the potential risks. 
• Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms. However, despite potential dangers may be used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh risks over benefits. The drug is not for pregnant women. 
• Category N: No data is available for the drug under this category. 

Pharmacology

Pharmacology: 

sonidegib is a small molecule inhibitor of the Hedgehog signaling pathway. This pathway plays a critical role in cell growth and differentiation, and its dysregulation has been implicated in several types of cancers, including basal cell carcinoma (BCC). 

By inhibiting the Hedgehog signaling pathway, sonidegib reduces the proliferation of cancer cells and induces apoptosis (programmed cell death). This leads to a reduction in tumor size and an improvement in patient outcomes. 

sonidegib is administered orally and is absorbed in the gastrointestinal tract. It is metabolized primarily in the liver by the cytochrome P450 (CYP) 3A4 enzyme system and eliminated through the feces (65%) and urine (23%). 

The pharmacokinetics of sonidegib are dose-proportional over the therapeutic dose range. Steady-state concentrations are achieved within 2-3 weeks of daily dosing. The half-life of sonidegib is approximately 30 hours. 

sonidegib has a black box warning for embryo-fetal death or severe birth defects when administered to a pregnant woman. It is also associated with several potential side effects, including muscle spasms, arthralgia, myalgia, alopecia, dysgeusia, and fatigue. sonidegib can also cause QT prolongation, which is a potential risk factor for arrhythmias. 

Pharmacodynamics: 

The pharmacodynamics of sonidegib are mainly related to its inhibition of the Hedgehog signaling pathway. This pathway plays a critical role in cell growth and differentiation, and its dysregulation has been implicated in several types of cancers, including basal cell carcinoma (BCC). By inhibiting the Hedgehog signaling pathway, sonidegib reduces the proliferation of cancer cells and induces apoptosis (programmed cell death). This leads to a reduction in tumor size and an improvement in patient outcomes. 

sonidegib has been shown to inhibit the transcriptional activity of the Hedgehog signaling pathway in tumor cells, which leads to the downregulation of downstream target genes, including GLI1 and PTCH1. GLI1 is a transcription factor that plays a key role in the regulation of cell proliferation and differentiation, and its overexpression has been linked to tumorigenesis. PTCH1 is a receptor for the Hedgehog signaling pathway and is involved in the negative regulation of GLI1. 

In addition to its effects on the Hedgehog signaling pathway, sonidegib has been shown to inhibit the efflux transporter P-glycoprotein (P-gp), which is involved in the cellular transport of a variety of drugs. By inhibiting P-gp, sonidegib may increase the intracellular accumulation of other drugs, potentially leading to drug interactions.  

Pharmacokinetics: 

Absorption 

Less than 10% of the oral dose is absorbed 

The time to achieve peak plasma concentration is 2-4 hours (in fasting) 

The peak plasma concentration is 1030 ng/mL 

The minimum plasma concentration is 890 ng/mL 

The area under the curve is 22 mcg·h/mL 

Distribution 

Protein bound is more than 97% 

The volume of distribution is 9,166 L 

Metabolism 

The drug is primarily metabolized by CYP3A 

Elimination and Excretion 

The half-life of the drug is 28 days 

The drug is excreted 70% in feces and 30% urine 

Adminstartion

Administration: 

sonidegib is a prescription medication used to treat a type of skin cancer called basal cell carcinoma (BCC). It works by inhibiting the hedgehog signaling pathway, which plays a role in the growth and proliferation of cancer cells. 

sonidegib is available in the form of oral capsules and should be taken once a day, at the same time each day. The capsules should be swallowed whole with water and can be taken with or without food. 

The dosage of sonidegib prescribed will depend on a variety of factors, including the patient’s age, weight, overall health, and the severity of their BCC. Your healthcare provider will determine the appropriate dose and duration of treatment for you. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: sonidegib (Rx) 

Pronounced: SOE-ni-DEG-ib 

Why do we use sonidegib? 

sonidegib is a medication that is used to treat a type of skin cancer called basal cell carcinoma (BCC). BCC is the most common form of skin cancer, and it typically grows slowly and rarely spreads to other parts of the body. However, if left untreated, BCC can cause significant damage to surrounding tissue and bone. 

sonidegib works by inhibiting a signaling pathway called the hedgehog pathway, which is involved in the growth and proliferation of cancer cells. By blocking this pathway, sonidegib can help to slow or stop the growth of BCC tumors. 

sonidegib is typically used to treat BCC that cannot be surgically removed, or that has spread to other parts of the body. It may also be used to treat BCC that has come back after previous treatment. Your healthcare provider will determine if sonidegib is appropriate for your specific situation and provide guidance on how to take the medication safely and effectively.