Glasdegib – Uses, Dosage, Side Effects, Interaction

Glasdegib Maleate is the maleate salt form of glasdegib, an orally bioavailable small-molecule, smoothened (SMO) receptor inhibitor, with potential antineoplastic activity. Upon oral administration, glasdegib targets bind to and inhibit the activity of SMO. This inhibits the activity of the Hedgehog (Hh) signaling pathway and inhibits the growth of tumor? cells in which this pathway is aberrantly activated. SMO, a transmembrane protein, is involved in Hh signal transduction. The Hh signaling pathway plays an important role in cellular growth, differentiation, repair, and cancer stem cell (CSC) survival. Constitutive activation of Hh pathway signaling has been observed in various types of malignancies and is associated with uncontrolled cellular proliferation in a variety of cancers.

Glasdegib, also known as PF-04449913, is a small-molecule hedgehog signaling inhibitor selected under the group of benzimidazoles. In early research, benzimidazoles attracted large interest as they represented a class of inhibitors with low molecular weight, potent inhibitory activity and lacking unstable functionality. The great lipophilicity of this group of compounds brought interest to further modification. This analysis concluded that the presence of p-cyano ureas presented good physicochemical and pharmacokinetic properties from which glasdegib was developed.^[rx]Glasdegib was developed by Pfizer Inc and approved on November 21, 2018, by the FDA for the treatment of Acute Myeloid Leukemia.^[rx]

In preclinical studies, glasdegib achieved a significant reduction in leukemic stem cell burden in xenograft models and a reduction in the cell population expressing leukemic stem cell markers. In clinical? trials, glasdegib demonstrated a marked downregulation of more than 80% of the expression of glioma-associated transcriptional regulator GL11 in the skin. In this same study, 8% of the studied individuals with acute myeloid leukemia achieved morphological complete remission? while 31% achieved a stable disease state. The latest clinical trial proved glasdegib to generate an overall survival of 8.3 months which was almost double what has been observed in patients under low-dose cytarabine treatment. As well, there have been reports of dose-dependent QTc prolongation in patients administered with glasdegib.

Use in Cancer

Glasdegib maleate is approved to treat:

• Acute myeloid leukemia that is newly diagnosed. It is used with low-dose cytarabine in patients aged 75 years and older or adults who cannot be treated with intensive induction chemotherapy.

Glasdegib maleate is also being studied in the treatment of other types of cancer.

Contraindications

• are allergic to glasdegib or any ingredients of the medication
• are male and are unwilling or unable to use effective birth control?
• are female, may become pregnant, and are unwilling or unable to use effective birth control
• are pregnant
• are breast-feeding
• low amount of magnesium in the blood
• low amount of potassium in the blood
• prolonged QT interval on EKG
• chronic heart failure?
• abnormal EKG with QT changes from birth
• pregnancy
• a patient who is producing milk and breastfeeding

Dosage?

Strengths: 25 mg; 100 mg

Acute Myeloid Leukemia

• 100 mg orally once a day on days 1 to 28 in combination with cytarabine 20 mg subcutaneously 2 times a day on days 1 to 10 of each 28-day cycle in the absence of unacceptable toxicity or loss of disease control; for patients without unacceptable toxicity, treat for a minimum of 6 cycles to allow time for clinical response=

Acute Myeloid Leukemia

75 years or older:

• 100 mg orally once a day on days 1 to 28 in combination with cytarabine 20 mg subcutaneously 2 times a day on days 1 to 10 of each 28-day cycle in the absence of unacceptable toxicity or loss of disease control; for patients without unacceptable toxicity, treat for a minimum of 6 cycles to allow time for clinical response

Dose Adjustments

Dose Modifications for Adverse Reactions:
QTC INTERVAL PROLONGATION ON AT LEAST 2 SEPARATE ELECTROCARDIOGRAMS (ECGS):

• QTc interval greater than 480 ms to 500 ms: Assess electrolyte levels as clinically indicated; review and adjust concomitant medications with known QTc interval-prolonging effects; monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation to less than or equal to 480 ms.
• QTc interval greater than 500 ms: Assess electrolyte levels and supplement as clinically indicated; review and adjust concomitant medications with known QTc interval-prolonging effects; interrupt therapy; resume therapy at a reduced dose of 50 mg once daily when QTc interval returns to within 30 ms of baseline? or less than or equal to 480 ms; monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation; consider re-escalating the dose to 100 mg daily if an alternative etiology for the QTc prolongation can be identified.
• QTc interval prolongation with life-threatening arrhythmia?: Permanently discontinue therapy.

HEMATOLOGIC TOXICITY:

• Platelets less than 10 GI/L for more than 42 days in the absence of disease: Discontinue this drug and low-dose cytarabine permanently.
• Neutrophil? count less than 0.5 GI/L for more than 42 days in the absence of disease: Discontinue this drug and low-dose cytarabine permanently.

NONHEMATOLOGIC TOXICITY:

• Grade 3: Interrupt this drug and/or low-dose cytarabine until symptoms reduce to mild? or return to baseline; resume this drug at the same dose level, or at a reduced dose of 50 mg; resume low-dose cytarabine at the same dose level, or at a reduced dose of 10 or 15 mg; if toxicity recurs, discontinue this drug and low-dose cytarabine; if toxicity is attributable to this drug only, low-dose cytarabine may be continued.
• Grade 4: Discontinue this drug and low-dose cytarabine permanently.

DOSE MODIFICATION FOR CONCOMITANT USE WITH MODERATE CYP450 3A4 INDUCERS:

• Avoid concomitant use of this drug with moderate CYP450 3A4 inducers.
• If concomitant use cannot be avoided, increase the dose of this drug as tolerated as shown below:
• After the moderate CYP450 3A4 inducer has been discontinued for 7 days, resume this drug at the dose taken prior to initiating the moderate CYP450 3A4 inducer.

DOSE MODIFICATION OF THIS DRUG WHEN TAKEN WITH MODERATE CYP450 INDUCERS:

• If the current dose is 100 mg once a day: Increase it to 200 mg orally once a day.
• If the current dose is 50 mg orally once a day: Increase it to 100 mg orally once a day.

Administration advice:

• This drug may be taken with or without food.
• Do not split, divide, or crush tablets.
• Administer at the same time each day.
• If a dose is vomited, do not administer a replacement dose; wait until the next scheduled dose is due.
• If a dose is missed or not taken at the usual time, administer the dose as soon as possible and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day.
• Do not administer 2 doses within 12 hours.

Monitoring?:

• Assess complete blood counts, electrolytes, renal?, and hepatic function prior to the initiation of therapy and at least once a week for the first month.
• Monitor electrolytes and renal function once monthly for the duration of therapy.
• Obtain serum creatine kinase levels prior to initiating therapy and as indicated clinically thereafter (e.g., if muscle symptoms are reported).
• Monitor electrocardiograms (ECGs) prior to the initiation of therapy, approximately 1 week after initiation, and then once monthly for the next 2 months to assess for QTc prolongation. Repeat ECG? if abnormal. Some patients may require more frequent and ongoing ECG monitoring.

Side Effects

The Most Common

• muscle spasms
• muscle, bone or joint pain?
• extreme tiredness
• nausea?
• vomiting?
• abdominal pain?
• constipation?
• pain or sores in your mouth or throat?
• decreased appetite
• change in the way things taste
• weight loss?
• headache
• rash
• swelling of hands or legs
• hair loss
• toothache
• feeling faint, lightheaded, or dizzy; fast or irregular heartbeat
• unusual bruising or bleeding
• fever alone or along with chills, and weakness. or other signs of infection
• decreased urination
• chest pain

More common

• Black, tarry stools
• bleeding gums
• blood in the urine or stools
• chest pain
• chills
• confusion
• cough
• coughing up blood
• decreased frequency or amount of urine
• difficult or labored breathing
• difficulty in swallowing
• dizziness or fainting
• drowsiness
• dry mouth
• fainting
• fast, slow, or irregular heartbeat
• fever
• headache
• increased blood pressure
• increased menstrual flow or vaginal bleeding
• increased thirst
• lightheadedness
• loss of appetite
• loss of consciousness
• lower back or side pain
• mood or mental changes
• muscle pain or cramps
• muscle spasms (tetany) or twitching seizures
• nausea
• nervousness
• nosebleeds
• numbness or tingling in the hands, feet, or lips
• painful or difficult urination
• pale skin
• paralysis
• pinpoint red spots on the skin
• pounding heartbeat
• prolonged bleeding from cuts
• rapid, shallow breathing
• red or black, tarry stools
• red or dark brown urine
• seizures
• sneezing
• sore throat
• stomach pain
• swelling of the face, hands, ankles, or lower legs
• tightness in the chest
• trembling
• troubled breathing with exertion
• ulcers, sores, or white spots in the mouth
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting
• weakness or heaviness of the legs
• weight gain
• Bone or muscle pain
• change in taste
• constipation
• cracked lips
• decreased appetite
• diarrhea
• loose tooth
• loss of taste
• skin rash
• thinning or loss of hair
• toothache

Rare

• changes in sense of taste
• decreased appetite
• fatigue
• hair loss
• headache
• muscle, joint, or bone pain
• muscle spasms or tightness
• nausea
• rash
• sores or pain in the mouth or throat
• stomach pain
• toothache or lose tooth
• weakness
• weight loss
• irregular heartbeat (e.g., fast, slow, or pounding heartbeat; shortness of breath; dizziness)
• signs of anemia (low red blood cells; e.g., dizziness, pale skin, unusual tiredness or weakness, shortness of breath)
• signs of clotting problems (e.g., unusual nosebleeds, bruising, blood in urine, coughing blood, bleeding gums, cuts that don’t stop bleeding)
• signs of infection (symptoms may include fever or chills, severe diarrhea, shortness of breath, prolonged dizziness, headache, stiff neck, weight loss, or listlessness)
• signs of kidney failure (e.g., decreased urine production, swelling, fatigue, abdominal pain)
• swelling arms, legs, face
• symptoms of low sodium levels in the blood (e.g., achy, stiff, or uncoordinated muscles; confusion; tiredness; weakness)
• symptoms of pneumonia (e.g., fever or chills, shortness of breath, fatigue, chest pain, cough)
• eye bleeding (e.g., blurred vision, pain when exposed to light, eye bruising)
• severe breathing problems (respiratory failure: blue color to skin, lips, or fingernails; sleepiness; irregular heartbeat; shortness of breath; loss of consciousness)
• signs of bleeding in the stomach (e.g., bloody, black, or tarry stools; spitting up blood; vomiting blood or material that looks like coffee grounds)
• signs of bleeding in the brain (e.g., sudden or severe headache; sudden loss of coordination; vision changes; sudden slurring of speech; or unexplained weakness, numbness, or pain in arm or leg)
• signs of a heart attack (e.g., sudden chest pain or pain radiating to back, down arm, jaw; sensation of fullness of the chest; nausea; vomiting; sweating; anxiety)

Drug Interactions

Drug-Food Interactions

Pregnancy and Lactation

US FDA pregnancy category: Not assigned.

Pregnancy

This medication should not be used during pregnancy, as it may cause harm to the developing baby. This drug can harm a developing fetus.
Verify negative pregnancy status in females of reproductive potential within 7 days prior to initiating therapy. Advise females of reproductive potential to use effective contraception during therapy and for at least 30 days after the last dose. Advise males of the potential risk of exposure through semen and to use effective contraception, including a condom, even after a vasectomy, to avoid drug exposure to a pregnant partner or a female partner of reproductive potential during therapy and for at least 30 days after the last dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. It is not known if this drug is present in semen. Advise males to not donate semen during therapy and for at least 30 days after the last dose. This drug may impair fertility in males of reproductive potential. Men should seek advice on effective fertility preservation before beginning therapy.

Lactation

It is not known if glasdegib passes into breast milk. Breastfeeding is not recommended while taking this medication. There are no data on the presence of this drug or its active metabolites in human milk, the effects of the drug on the breastfed child, or its effect on milk production. Because of the potential for serious adverse reactions in a breastfed child, women taking this drug should not breastfeed during therapy and for at least 30 days after the last dose.

References