Action and Spectrum

Actions and Spectrum: 

Actions: 

The main action of glasdegib is to inhibit the activity of the Smoothened (SMO) protein, which is a key component of the Hedgehog pathway. By blocking SMO, glasdegib can prevent the downstream activation of the GLI transcription factors, which are responsible for regulating the expression of genes involved in cell growth and survival. 

Spectrum: 

The spectrum of glasdegib’s activity is primarily focused on cancers that are driven by abnormal activation of the Hedgehog pathway. This includes cancers with mutations in the SMO or GLI genes, as well as tumors that secrete Hedgehog ligands to stimulate the pathway.

However, glasdegib may also have activity against other types of cancer, particularly those that have mutations in other signaling pathways that crosstalk with the Hedgehog pathway. Ongoing research is aimed at identifying biomarkers that can help predict which patients are most likely to benefit from treatment with glasdegib. 

Drug Interaction

Adverse Reaction

Frequency defined: 

>10% 

Edema 

Atrial arrhythmia 

Chest pain 

Fatigue 

Dizziness 

Headache 

Skin rash 

Hyponatremia 

Hyponatremia 

Hypomagnesemia 

Hyperkalemia 

Hypokalemia 

Weight Loss 

Nausea 

Decreased appetite 

Dysgeusia 

Mucositis 

Constipation 

Abdominal pain 

Diarrhea 

Vomiting 

Anemia 

Hemorrhage 

Febrile neutropenia 

Thrombocytopenia 

Decreased WBC 

Musculoskeletal pain 

Muscle spasm 

Renal insufficiency 

Dyspnea 

Pneumonia 

Cough 

Fever 

1-10% 

Prolonged QT interval 

Sepsis 

Black Box Warning

Black Box Warning: 

Embryo-fetal toxicity 

• glasdegib can cause severe birth defects or embryo-fetal death. The effects may happen in pregnant women if the dose is administered to them. The drug is fetotoxic, embryotoxic and teratogenic in animals 
• Before initiating medication take pregnancy test in females of reproductive potential  
• it is important for healthcare providers to advise fertile females to utilise an effective contraceptive measure during glasdegib treatment. This will help to minimize the risk of unintended pregnancy during treatment. 
• Similarly, males who are receiving treatment with glasdegib should be advised of the potential risk of exposure to their pregnant partner or fertile female partner through semen. They should use condoms during sexual activity to prevent potential exposure during treatment.

Contraindication / Caution

Contraindication/Caution: 

Contraindications: 

Hypersensitivity 

Caution: 

• Hepatic impairment: glasdegib is metabolized primarily in the liver, and caution should be exercised in patients with hepatic impairment. 
• Renal impairment: glasdegib is eliminated primarily through the kidneys, and caution should be exercised in patients with renal impairment. 
• QT prolongation: glasdegib can cause prolongation of the QT interval, which can lead to serious cardiac arrhythmias. Therefore, it should be used with caution in patients with a history of QT prolongation, those taking medications that can prolong the QT interval, or those with electrolyte imbalances. 
• Drug interactions: glasdegib is metabolized by the CYP3A4 enzyme system and can interact with other medications that inhibit or induce this enzyme system. Therefore, caution should be exercised when co-administering glasdegib with medications that are strong inhibitors or inducers of CYP3A4. 
• Embryo-fetal toxicity: As mentioned earlier, glasdegib can cause fetal harm when administered to a pregnant woman. Therefore, pregnancy should be avoided during treatment with glasdegib, and effective contraception should be used during the medication. 

Pregnancy / Lactation

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

It inhibits the Hedgehog pathway, which is critical for fetal development. 

Lactation: No data available regarding the excretion of glasdegib in breast milk. Hence, potential adverse effects and potential benefits should be compared and considered. 

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: 

glasdegib is a small molecule inhibitor of the Hedgehog signaling pathway. It works by binding to the Smoothened (SMO) protein, a key component of the Hedgehog pathway, and blocking its activity. This prevents the downstream activation of the GLI transcription factors, which are responsible for regulating the expression of genes involved in cell growth and survival. 

Pharmacodynamics: 

The primary pharmacodynamic effect of glasdegib is inhibition of the Hedgehog signaling pathway. The Hedgehog pathway plays a key role in regulating cell growth and differentiation during embryonic development and is also involved in the development of certain types of cancer. 

Inhibition of the Hedgehog pathway by glasdegib leads to downstream effects on the GLI transcription factors, which are responsible for regulating the expression of genes involved in cell growth and survival. By inhibiting the activity of the Hedgehog pathway, glasdegib can slow or stop the growth of cancer cells. 

Pharmacokinetics: 

Absorption 

Following oral administration, glasdegib is rapidly absorbed and reaches peak plasma concentrations within 2 to 4 hours. 

Distribution 

Protein-bound is 91% 

The volume of distribution is 188L 

Metabolism 

It is extensively metabolized by the liver, primarily through the CYP3A4, CYP2C8, and UGT1A9. 

Elimination and Excretion 

It is eliminated mainly through the feces (42%) and in urine (49%) 

Adminstartion

Administration:

glasdegib is administered orally in the form of tablets. The recommended dose of glasdegib is 100 mg once daily, taken at approximately the same time each day, with or without food. The tablets should be swallowed whole and not crushed, broken, or chewed. 

If a patient misses a dose of glasdegib, they should take it as soon as they remember. However, if it is less than 12 hours until the next scheduled dose, they should skip the missed dose and resume their usual dosing schedule. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: glasdegib 

Pronounced: glas-DEG-ib 

Why do we use glasdegib? 

glasdegib is a medication used to treat certain types of blood cancers, specifically acute myeloid leukemia (AML), in adults who are 75 years or older or who have certain medical conditions that make them ineligible for intensive chemotherapy.