Glasdegib: Uses, Effects, Mechanism of Action, Drug Interactions, Advantages, and Disadvantages

Overview:

Glasdegib, classified as a hedgehog pathway inhibitor, is administered in combination with Cytarabine as an initial treatment for acute myeloid leukemia (AML). The United States Food and Drug Administration (FDA) has approved Glasdegib, in combination with low-dose Cytarabine (LDAC), for the treatment of newly diagnosed acute myeloid leukemia (AML) in elderly patients who cannot undergo intensive chemotherapy. This combined therapy aims to inhibit the hedgehog pathway and enhance the anti-leukemic effects. This therapeutic approach is specifically targeted toward individuals over 75 years old or adults with underlying medical conditions that prevent the use of alternative chemotherapy medications.

This article presents a synopsis of the mechanism of action, preclinical and clinical studies, and the current status of Glasdegib as a therapeutic option for AML. The efficacy and safety profile of Glasdegib, both as a monotherapy and in combination with other agents, are discussed. Additionally, the challenges and future directions for its implementation in clinical practice are explored.

Drug Group:

Glasdegib is categorized as a hedgehog pathway inhibitor drug. It is a powerful and specific inhibitor of the hedgehog signaling pathway, which has exhibited promising outcomes in clinical studies. By specifically targeting the atypical signaling pathway involved in the advancement and spread of acute myeloid leukemia (AML), Glasdegib has the potential to disrupt the proliferation and viability of leukemic cells.

Available Doses and Dosage Forms:

Glasdegib is available in oral tablet form. The recommended dosage of Glasdegib for the treatment of acute myeloid leukemia (AML) is typically 100 mg (milligram) taken orally once daily, usually taken in combination with Cytarabine.

For Patients:

What Is Acute Myeloid Leukemia?

Acute myeloid leukemia (AML) is a cancer that affects predominantly the bone marrow and blood cells. It is characterized by the fast growth of abnormal myeloid cells, which are a type of white blood cell. The body's defense against infections is carried out by white blood cells (WBCs). In the case of acute myeloid leukemia (AML), individuals experience an abnormal accumulation of these cells in the bone marrow. This excessive accumulation hinders the production of healthy blood cells. The exact cause of AML is often unknown, but certain risk factors can increase the likelihood of developing the disease. These risk factors include exposure to radiation or certain chemicals, previous chemotherapy or radiation therapy, certain genetic disorders, and some blood disorders.

There are several subtypes of acute myeloid leukemia, which are classified based on the specific characteristics of the leukemia cells. Here are some common subtypes of AML:

1. AML With Recurrent Genetic Abnormalities: This subtype includes AML cases with specific chromosomal abnormalities, such as translocations or mutations involving certain genes, such as FLT3 (FMS-like tyrosine kinase 3), NPM1 (nucleophosmin 1), or CEBPA (CCAAT/enhancer-binding protein alpha).

2. AML With Myelodysplasia-related Changes: This subtype is characterized by the presence of genetic changes similar to those seen in myelodysplastic syndromes (a type of cancer of the blood in which the body's production of healthy blood cells is insufficient).

3. Therapy-Related AML: This subtype occurs as a result of previous treatment with chemotherapy or radiation therapy for another condition, such as a different type of cancer.

4. AML Not Otherwise Specified (NOS): This category includes cases of AML that do not fall into the other specific subtypes.

The signs and symptoms of AML may include fatigue, shortness of breath, frequent infections, easy bruising or bleeding, bone pain, and unexplained weight loss. AML is typically diagnosed through blood tests, bone marrow biopsy, and genetic testing. Common treatment approaches include chemotherapy, targeted therapy, stem cell transplant, and supportive care to manage symptoms and complications.

How Does Glasdegib Work?

Glasdegib works by selectively inhibiting the hedgehog signaling pathway (transmits information to embryonic cells required for cell differentiation), which is involved in cellular growth and development. The Hedgehog pathway has a key protein name, smoothened (SMO), Glasdegib blocks this protein. By blocking a key protein called smoothened (SMO), Glasdegib disrupts the communication between cancer cells, reducing their growth and survival.

What Is the Dosage of Glasdegib?

For the treatment of acute myeloid leukemia (AML), Glasdegib is commonly prescribed at a daily oral dosage of 100 mg.

How Effective Is Glasdegib?

Glasdegib has shown effectiveness in the treatment of acute myeloid leukemia (AML) when used in combination with Cytarabine, a standard chemotherapy medication. Clinical trials have substantiated that incorporating Glasdegib into Cytarabine can improve outcomes in certain patient populations. In particular, Glasdegib, in combination with Cytarabine, has been studied in older adults with newly diagnosed AML who are not eligible for intensive chemotherapy regimens. This combination therapy has been shown to increase overall survival rates and improve complete remission rates compared to Cytarabine alone.

Clinical studies have assessed the effectiveness of Glasdegib in treating acute myeloid leukemia (AML). One pivotal study, known as the BRIGHT AML 1003 trial, evaluated the combination of Glasdegib and low-dose Cytarabine (LDAC) compared to LDAC alone in older patients with AML who were unsuitable for intensive chemotherapy. The results of the BRIGHT AML 1003 trial showed that the combination therapy of Glasdegib and LDAC significantly improved overall survival compared to LDAC alone. Patients receiving Glasdegib in combination with LDAC had a median overall survival of 8.3 months, whereas those receiving LDAC alone had a median overall survival of 4.3 months. This demonstrated a substantial benefit in terms of prolonging survival for patients receiving Glasdegib in combination therapy.

Furthermore, the study also reported an increased complete remission rate in patients treated with the Glasdegib and LDAC combination compared to LDAC alone. Complete remission is the absence of detectable leukemia cells in the bone marrow. These findings indicate that Glasdegib, when used in combination with LDAC, has shown efficacy in improving overall survival and achieving complete remission in older patients with AML who are unsuitable for intensive chemotherapy.

What Are the Things to Inform the Doctor Before Taking the Drug?

Before taking Glasdegib, please consider the following important information:

1. Allergies: Inform the doctor about any allergies to Glasdegib, other medications, or any ingredients in Glasdegib tablets. Consult the medication guide for a list of ingredients available with the healthcare professional.

2. Medications: Inform the doctor and pharmacist about all prescription and nonprescription medications, as well as vitamins and supplements, that the patient is currently taking or planning to take. It is especially important to mention medications such as Amiodarone, Carbamazepine, Chlorpromazine, Cilostazol, Citalopram, Clarithromycin, Disopyramide, Dofetilide, Donepezil, Dronedarone, Efavirenz, Escitalopram, Flecainide, Fluconazole, Haloperidol, Ibutilide, Indinavir, Itraconazole, Ketoconazole, Methadone, Nefazodone, Nelfinavir, Nevirapine, Ondansetron, Phenobarbital, Phenytoin, Pimozide, Pioglitazone, Procainamide, Quinidine, Rifabutin, Rifampin, Ritonavir, Sotalol, and Thioridazine. The doctor may need to adjust dosages or closely monitor for potential side effects. It is important to disclose all medications, even those not listed, to the doctor the patient is consulting.

3. Herbal Products: Inform the doctor about consuming herbal products, especially St. John's wort.

4. Medical Conditions: Discuss with the doctor if there is a history of prolonged QT interval (a rare heart condition that can cause irregular heartbeat, fainting, or sudden death), heart failure, or insufficient levels of magnesium or potassium can be observed in the patient’s blood.

5. Breastfeeding: If the patient is currently breastfeeding, it is recommended to abstain from breastfeeding during Glasdegib treatment and for a minimum of 30 days following the last dose.

6. Fertility Considerations: It is necessary to understand that Glasdegib may decrease fertility in men. Talk to the doctor about any concerns or risks associated with taking Glasdegib.

How Is Glasdegib Administered?

Glasdegib is typically taken once a day, with or without food, for at least six months or as directed by the doctor. Consistency in taking Glasdegib at the same time every day is crucial. Adhere diligently to the instructions on the prescription label, and if there is anything do not understand, consult the doctor or pharmacist for clarification. Take Glasdegib exactly as prescribed, neither more nor less, and avoid exceeding the recommended frequency. The tablets should be swallowed whole. Do not take an additional dose if the person vomits after taking Glasdegib. Just maintain the regular dosing schedule as prescribed.

What Are the Side Effects of Glasdegib?

Following side effects while taking Glasdegib, it is important to notify the doctor, as they may be severe or persistent:

• Muscle spasms.

• Muscle, bone, or joint pain.

• Extreme tiredness.

• Nausea.

• Vomiting.

• Abdominal pain.

• Constipation.

• Discomfort or ulcers in the mouth or throat.

• Decreased appetite.

• Change in taste.

• Weight loss.

• Headache.

• Rash.

• Swelling of hands or legs.

• Hair loss.

• Toothache.

Some side effects can be serious, and immediate medical attention should be sought as soon as they are experienced:

• Feeling faint, lightheaded, or dizzy.

• Fast or irregular heartbeat.

• Unusual bruising or bleeding.

• Fever accompanied by chills, weakness, or signs of infection.

• Decreased urination.

• Chest pain.

It is important to note that Glasdegib may cause other side effects not listed here. If the person taking Glasdegib has any unusual problems while taking this medication, contact the doctor for further evaluation and guidance.

Dietary Considerations:

There are no specific dietary considerations or restrictions associated with Glasdegib unless the doctor has recommended any change. However, it is always important to maintain a healthy and balanced diet and adequate hydration during the treatment of acute myeloid leukemia (AML).

Missed Dose:

Try not to miss any dose. In the event of a missed dose, take it promptly as soon as remember. If it is time for the next day's dose, skip the previously missed dose and follow the regular dosing. It is important to avoid doubling the dosage to compensate for any missed doses.

Overdose:

In the event of an overdose of Glasdegib or the occurrence of severe symptoms like intense dizziness, loss of consciousness, or breathing difficulties, it is imperative to seek immediate medical assistance or get in touch with the local poison control center. The management approach usually involves providing supportive care, closely monitoring the patient's condition, and administering symptomatic treatment if necessary, depending on the severity of the symptoms. If the ingestion of the medication was recent, gastric decontamination methods may be considered. Always follow the guidance and instructions of healthcare professionals in such situations.

Storage:

Please ensure to store this medication in its original packing, including the container, tightly closed, and in a secure place that is out of reach of children. Keep the medicine at room temperature and protect it from excessive heat and moisture. Always remember to store all medications in a child-resistant manner, using safety caps and keeping them out of sight and reach of children. To prevent accidental ingestion, ensure the proper disposal of any unused medication. Please refrain from disposing of the medication by flushing it down the toilet. Instead, consider consulting the pharmacist or reaching out to the local garbage/recycling department to inquire about medicine take-back programs offered in the neighboring community.

For Doctors:

Indication:

Glasdegib is indicated for the treatment of adult patients with newly diagnosed acute myeloid leukemia in the geriatric population of patients aged above 75 years, or who have medical conditions that make them ineligible for intensive induction chemotherapy. It is used in combination with low-dose Cytarabine, another chemotherapy medication.

Dose:

The recommended dose for Glasdegib is 100 mg taken orally once daily.

Dosing Considerations:

QTc Interval Prolongation:

1. If the QTc interval is between 480 ms (milliseconds) and 500 ms on at least two separate ECGs, check electrolyte levels and supplement if needed. Review and adjust medications that may prolong QTc interval. Monitor ECGs (electrocardiogram) weekly for two weeks after QTc prolongation resolves.

2. If the QTc interval is greater than 500 ms, check electrolyte levels and supplement if needed. Review and adjust medications that may prolong QTc interval. Temporarily stop Glasdegib treatment.

3. Once the QTc interval returns to within 30 ms of the baseline or is equal to or less than 480 ms (milliseconds), the patient can resume Glasdegib at a reduced dosage of 50 mg once daily. Monitor ECGs (electrocardiograms) weekly for two weeks after QTc prolongation resolves.

4. Consider increasing the dose to 100 mg daily if an alternative cause for QTc prolongation is found.

5. QTc Interval Prolongation with Life-Threatening Arrhythmia: For this situation, it is advised to stop Glasdegib permanently.

Hematologic Toxicity:

If the platelet count remains below 10 Gi/L (gigagrams per liter) for a period exceeding 42 days without the presence of the disease, it is recommended to discontinue the use of Glasdegib and low-dose Cytarabine permanently.

Neutrophil Count:

If the neutrophil count is less than 0.5 Gi/L for more than 42 days without the disease, it is advised to discontinue Glasdegib and low-dose Cytarabine permanently.

Nonhematologic Toxicity (Grades 3 and 4):

1. Grade 3 Toxicity: Nonhematologic Grade 3 toxicity refers to severe side effects or complications unrelated to the blood system. It can include severe gastrointestinal, cardiovascular, hepatic, renal, neurologic, pulmonary, or dermatologic symptoms. In case of this toxicity, temporarily suspend the administration of Glasdegib and/or low-dose Cytarabine until symptoms show improvement or return to their previous baseline. Upon resuming treatment, Glasdegib should be reintroduced at the original dosage or a reduced dose of 50 mg. Similarly, low-dose Cytarabine can be resumed at the original dose or a reduced dose of 15 mg or 10 mg. In the case of recurrent toxicity, it is advisable to discontinue both medications. However, if the toxicity is solely attributed to Glasdegib, low-dose Cytarabine may continue to be administered.

2. Grade 4 Toxicity: Grade 4 non-hematologic toxicity indicates a critical and life-threatening level of severe adverse effects outside the blood system. It requires immediate medical attention and may involve severe complications affecting various organs or functions. It is recommended to stop Glasdegib and low-dose Cytarabine permanently.

What Are the Pharmacological Aspects of Glasdegib?

Pharmacodynamics:

In preclinical studies, Glasdegib has shown a significant decrease in leukemic stem cell burden in animal models and a reduction in the population of cells expressing leukemic stem cell markers. Clinical trials have demonstrated that Glasdegib effectively reduces the expression of the glioma-associated transcriptional regulator GL11 by more than 80 percent in the skin. In the same study, 8 percent of individuals with acute myeloid leukemia achieved complete remission, while 31 percent achieved a stable disease state. The latest clinical trial has revealed that Glasdegib leads to an overall survival of 8.3 months, nearly double that observed in patients treated with low-dose Cytarabine. It is important to note that there have been reports of QTc prolongation, which depends on the dosage of Glasdegib.

Mechanism:

Glasdegib is a selective inhibitor of the hedgehog signaling pathway. This pathway is a crucial signaling pathway involved in cellular growth and development. Moreover, it is pivotal in governing other biological processes, including embryonic development, tissue maintenance, and cell differentiation. In the case of cancer, aberrant activation of the hedgehog pathway can contribute to uncontrolled cell growth and tumor progression. Glasdegib specifically targets a protein called smoothened (SMO), which is a very important component of the hedgehog signaling pathway. By binding to SMO, Glasdegib will inhibit its activity and blocks the downstream signaling cascade. By inhibiting the hedgehog pathway, Glasdegib disrupts the intercellular communication between cancer cells and their immediate microenvironment, thus helping in reducing the growth and survival of cancer cells. This inhibition can lead to decreased proliferation, increased apoptosis (cell death), and impaired tumor growth.

Glasdegib is often used in combination with other therapies, such as chemotherapy, to enhance treatment outcomes. It has been approved for use in specific patient populations, including older adults with newly diagnosed acute myeloid leukemia (AML) who are not eligible for intensive chemotherapy. Overall, Glasdegib's mechanism of action lies in its ability to selectively inhibit the hedgehog signaling pathway, offering a targeted approach to combat cancer cell growth and improve treatment efficacy.

Pharmacokinetics:

• Absorption: Glasdegib shows dose-proportional pharmacokinetics, with a broad increase in plasma concentration as the dose increases. In studies using a 50 mg dose, it reached peak concentration in about 4 hours, with a corresponding exposure level. The oral bioavailability is approximately 55 percent. Absorption may be affected by a high-fat, high-calorie meal.

• Distribution: The reported volume of distribution of Glasdegib at a dose of 50 mg is 225 L (liters).

• Elimination: Approximately 49 percent of the administered dose of Glasdegib is eliminated through urine, with 17 percent being excreted unchanged. About 42 percent is eliminated through feces, with 20 percent being in the unchanged form.

• Clearance: The reported clearance rate of Glasdegib at a dose of 50 mg is 5.22 liters per hour.

Toxicity:

1. Overdose of Glasdegib typically occurs at doses starting from 640 mg/day (milligram per day) and may result in symptoms such as nausea, vomiting, dehydration, fatigue, and dizziness. In case of overdose, it is recommended to provide symptomatic treatment and monitor the patient's electrocardiogram (ECG). The oral LD50 (lethal dose for 50 percent of the tested population) of Glasdegib administered in triacetin has been reported to be 3000 mg/kg (milligrams per kilogram) in rats.

2. During Glasdegib therapy, it is common to observe elevations in serum ALT (alanine aminotransferase) levels. Approximately 31 percent of patients experience such elevations, with 11 percent of them exceeding five times the upper limit of the normal range. However, there have been no reported instances of acute liver injury or associated symptoms like jaundice specifically linked to the use of Glasdegib. It is important to note that due to the limited clinical experience with hedgehog inhibitors like Glasdegib, their potential for causing liver injury is not well-defined or thoroughly understood.

Clinical Studies:

The safety profile of Glasdegib is based on a study involving adults with newly-diagnosed AML. Among patients receiving Glasdegib with low-dose Cytarabine, a substantial 79 percent reported experiencing serious adverse reactions. The most frequently observed adverse reactions were febrile neutropenia, pneumonia, hemorrhage, anemia, and sepsis. Dose reductions and permanent discontinuation of treatment were reported in a portion of patients due to adverse reactions. However, it is important to note that these findings may not reflect the rates observed in real-world practice.

What Are the Contraindications of Glasdegib?

As such, no contraindications are documented.

Warnings and Precautions:

1. Blood Donation: While undergoing treatment with Glasdegib, patients should avoid donating blood or blood products for a minimum of one month following the last dose.

2. QTc Interval Prolongation: Regular monitoring of electrocardiograms and electrolyte levels is necessary. If QTc prolongation is observed, treatment with Glasdegib should be temporarily interrupted.

3. Embryo-Fetal Toxicity: Glasdegib can cause severe birth defects or death of the embryo or fetus if used during pregnancy. Before starting treatment of Glasdegib, pregnancy testing should be conducted on females of reproductive potential. Women with a reproductive potential need to use effective contraception during the treatment period and for a minimum of one month following the last dose. Male individuals should be mindful of the potential risk of drug exposure through semen. It is advised to use condoms when engaging in sexual activities with a pregnant partner or a female partner who has the potential for reproduction during the treatment period and for a minimum of one month following the last dose.

What Are the Drug Interactions of Glasdegib?

1. Strong CYP3A4 Inhibitors: It is recommended to explore alternative therapies that do not act as strong CYP3A4 inhibitors. If co-administration is necessary, close monitoring for potential adverse reactions, such as QTc interval prolongation, is advised.

2. Strong CYP3A4 Inducers: Concurrent use of Glasdegib with strong CYP3A4 inducers should be avoided.

3. QTc Prolonging Drugs: It is recommended to avoid the simultaneous administration of QTc prolonging drugs with Glasdegib. If co-administration cannot be avoided, careful monitoring for an increased risk of QTc interval prolongation is necessary.

Specific Considerations:

1. Pregnancy: Glasdegib can cause harm to the fetus when taken by pregnant women. It is not recommended to use Glasdegib during pregnancy. Pregnancy testing should be conducted before starting treatment with Glasdegib. Women of childbearing potential should utilize reliable contraception throughout the duration of the treatment period and for a minimum of one month following the last dose. Men should be aware of the potential risk of drug exposure through semen and should use effective contraception, including condoms, during the treatment period and for a minimum of one month following the last dose.
2. Lactation: There is no data available on the presence of Glasdegib in human milk or its effects on breastfed infants. It is advised to abstain from breastfeeding during Glasdegib treatment and for a minimum of one month following the final dose.
3. Reproductive Potential: Glasdegib carries the risk of fetal harm. Prior to initiating treatment, females who are capable of reproduction must undergo pregnancy testing. It is crucial for females to use effective contraception during the treatment period and for a minimum of one month following the final dose. Males should be cognizant of the potential hazard of drug exposure through semen and should practice reliable contraception, including condom use, throughout the treatment period and for at least 30 days after the final dose. During the treatment period and for a minimum of 30 days following the last dose, males should refrain from donating semen.
4. Pediatric Use: The safety and effectiveness of Glasdegib have not been established in pediatric patients.
5. Geriatric Use: The majority of patients in clinical studies of Glasdegib were 65 years or older, with a significant population being 75 years or older.