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General Description:

Glasdegib, identified by CAS number 1095173-27-5, is a notable compound with significant therapeutic applications. Glasdegib, also known as PF-04449913, is a small-molecule hedgehog signaling inhibitor selected under the group of the benzimidazoles. In early research, benzimidazoles attracted large interest as they represented a class of inhibitors with a 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. Glasdegib was developed by Pfizer Inc and approved on November 21, 2018, by the FDA for the treatment of Acute Myeloid Leukemia.

Indications:

This drug is primarily indicated for: Glasdegib, in combination with cytarabine, is indicated for the treatment of newly diagnosed acute myeloid leukemia in adult patients who are over 75 years old or that have co-morbidities that preclude intensive induction chemotherapy. Acute myeloid leukemia is characterized by abnormal production of myeloblasts, red cells, or platelets. It is considered a cancer of blood and bone marrow and it is the most common type of acute leukemia in adults. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Glasdegib undergoes metabolic processing primarily in: After oral administration, glasdegib was primarily metabolized by CYP3A4 with minor contributions of CYP2C8 and UGT1A9. The amount of unchanged glasdegib in plasma accounts only for 69% of the administered dose. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Glasdegib are crucial for its therapeutic efficacy: Glasdegib presents a dose-proportional pharmacokinetic profile which is observed by the presence of a broad dose-proportional maximum plasma concentration. In this study and on a dose of 50 mg, the median time to reach a maximum concentration of 321 ng/ml was of 4 hours with an AUC of 9587 ng.h/ml. The oral bioavailability of glasdegib is reported to be of 55%. In a multiple dose study of 50 mg, the Cmax, tmax and AUC was reported to be 542 ng/ml, 4 h and 9310 ng.h/ml respectively. In this same study, the average concentration at a steady state was of 388 ng/ml. The absorption rates of glasdegib can be modified by the concomitant consumption of a high-fat, high-calorie meal. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Glasdegib is an important consideration for its dosing schedule: The reported half-life of glasdegib is of 17.4 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Glasdegib exhibits a strong affinity for binding with plasma proteins: Glasdegib is reported to be 91% protein bounded which is explained due to its high lipophilic profile. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Glasdegib from the body primarily occurs through: From the administered dose of glasdegib, 49% is eliminated in the urine from which 17% is excreted as the unchanged form while 42% is eliminated in feces where 20% represents the unchanged form. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Glasdegib is distributed throughout the body with a volume of distribution of: Glasdegib reported volume of distribution in a dose of 50 mg is of 225 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Glasdegib is a critical factor in determining its safe and effective dosage: The clearance rate of 50 mg of glasdegib is reported to be of 5.22 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Glasdegib exerts its therapeutic effects through: In preclinical studies, glasdegib achieved a significant reduction in leukemic stem cell burden in xenograft models and a reduction in 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 skin. In this same study 8% of the studied individuals with acute myeloid leukemia achieved morphological complete remission while 31% achieved stable disease state. The latest clinical trial proved glasdegib to generate an overall survival of 8.3 months which was almost double to 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. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Glasdegib functions by: Glasdegib is a potent and selective inhibitor of the hedgehog signaling pathway that acts by binding to the smoothened (SMO) receptor. The hedgehog signaling pathway is involved in maintenance of neural and skin stem cells. In this pathway, the binding of specific ligands to the transmembrane receptor patched (PTCH1) allows the activation of the transcriptional regulators GL11, GL12 and modulation of the gene expression through SMO-mediated signaling. The aberrant activation of the hedgehog pathway is thought to be implicated in the pathogenesis of chronic myeloid leukemia, medulloblastoma and basal cell carcinoma due to the hyperproliferative state that a modification on this pathway will produce. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Glasdegib belongs to the class of organic compounds known as n-phenylureas. These are compounds containing a N-phenylurea moiety, which is structurally characterized by a phenyl group linked to one nitrogen atom of a urea group, classified under the direct parent group N-phenylureas. This compound is a part of the Organic compounds, falling under the Benzenoids superclass, and categorized within the Benzene and substituted derivatives class, specifically within the N-phenylureas subclass.

Categories:

Glasdegib is categorized under the following therapeutic classes: Amides, Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, BCRP/ABCG2 Inhibitors, BCRP/ABCG2 Substrates, Benzene Derivatives, Cytochrome P-450 CYP2C8 Substrates, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Substrates, Hedgehog Pathway Inhibitor, Hedgehog pathway inhibitors, Heterocyclic Compounds, Fused-Ring, Highest Risk QTc-Prolonging Agents, MATE 1 Inhibitors, MATE 2 Inhibitors, MATE inhibitors, P-glycoprotein inhibitors, P-glycoprotein substrates, QTc Prolonging Agents, Smoothened Receptor Antagonists, UGT1A9 Substrates. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Glasdegib include:

• Water Solubility: 0.02 mg/ml (in the form of di-HCl monohydrate salt)
• Melting Point: > 214 ºC
• Boiling Point: Decomposes at 214 ºC
• logP: 2.28
• caco2 Permeability: 0.00000598
• pKa: 6