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General Description:

Gilteritinib, identified by CAS number 1254053-43-4, is a notable compound with significant therapeutic applications. Gilteritinib, also known as ASP2215, is a small molecule part of the FLT3 tyrosine kinase inhibitors that presented a greater selectivity and potency when compared with other agents from this group. It is a pyrazinecarboxamide derivative that showed high selectivity to FLT3 preventing the c-Kit -driven myelosuppression observed in other therapies. Gilteritinib was developed by Astellas Pharma and FDA approved on November 28, 2018. This drug was approved after being designed as an orphan drug with a fast track and priority review status.

Indications:

This drug is primarily indicated for: Gilteritinib is indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia with an FLT3 mutation detected by an FDA-approved test. This indication was expanded for a companion diagnostic to include use with gilteritinib such as the LeukoStrat CDx FLT3 Mutation Assay. Acute myeloid leukemia is cancer that impacts the blood and bone marrow with a rapid progression. This condition produces low numbers of normal blood cells and the requirement of continuous need for transfusions. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Gilteritinib undergoes metabolic processing primarily in: Gilteritinib is primarily metabolized in the liver by the activity of CYP3A4. Its metabolism is driven by reactions of N-dealkylation and oxidation which forms the metabolite M17, M16 and M10. From the plasma concentration, the major form is the unchanged drug. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Gilteritinib are crucial for its therapeutic efficacy: In preclinical trials, the maximal plasma concentration of gilteritinib was observed 2 hours after oral administration and followed by a maximal intratumor concentration after 4-8 hours. The maximum concentration, as well as the AUC, were modified correspondingly with the dose and were reported to be 374 ng/ml and 6943 ng.h/ml, respectively. The steady-state plasma level is reached within 15 days of dosing with an approximate 10-fold bioaccumulation. In a fasted state in humans, the tmax is reported to be of 4-6 hours. The Cmax and AUC were decreased by 26% and 10% respectively by the co-ingestion of a high-fat meal with a tmax delay of 2 hours. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Gilteritinib is an important consideration for its dosing schedule: The reported median half-life of gilteritinib was of approximate 45-159 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Gilteritinib exhibits a strong affinity for binding with plasma proteins: Gilteritinib is reported to be highly bound to plasma proteins, representing 94% of the dose. From this ratio, the main protein-bound is serum albumin. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Gilteritinib from the body primarily occurs through: From the administered dose, gilteritinib is mainly excreted in feces which represents 64.5% of the administered dose while 16.4% is recovered in urine either as the unchanged drug or as its metabolites. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Gilteritinib is distributed throughout the body with a volume of distribution of: The estimated apparent central and peripheral volume of distribution is 1092 L and 1100 L respectively. This value indicated an extensive tissue distribution. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Gilteritinib is a critical factor in determining its safe and effective dosage: The estimated clearance of gilteritinib is 14.85 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Gilteritinib exerts its therapeutic effects through: In preclinical trials, gilteritinib demonstrate an IC50 for the wild-type receptor of 5 nM, 0.7-1.8 nM for ITD-mutated and comparable inhibition to other therapies in the TKD-mutated. As well, data showed a gilteritinib-driven inhibition of the receptor tyrosine kinase AXL which is known to modulate the activity of FLT3 in acute myeloid leukemia. Another important result _in vivo_ was the localization in high levels in xenografted tumors which indicated high selectivity. In phase 1/2 clinical trials, gilteritinib was shown to present a composite complete response of 41%, an overall response rate of 52%, a median duration of response of 20 weeks with a median overall survival of 31 weeks. In phase III clinical trials, gilteritinib reported a complete remission or complete remission with partial hematologic recovery in 21% of the patients. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Gilteritinib functions by: Gilteritinib is a potent selective inhibitor of both of the mutations, internal tandem duplication (ITD) and tyrosine kinase domain (TKD), of the FLT3 receptor. In the same note, gilteritinib also inhibits AXL and ALK tyrosine kinases. FLT3 and AXL are molecules involved in the growth of cancer cells. The activity of gilteritinib permits an inhibition of the phosphorylation of FLT3 and its downstream targets such as STAT5, ERK and AKT. The interest in FLT3 transmembrane tyrosine kinases was raised when studies reported that approximately 30% of the patients with acute myeloid leukemia presented a mutationally activated isoform. As well, the mutation ITD is associated with poor patient outcomes while the mutation TKD produces a resistance mechanism to FLT3 tyrosine kinase inhibitors and the AXL tyrosine kinase tends to produce a resistance mechanism to chemotherapies. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Gilteritinib belongs to the class of organic compounds known as phenylpiperidines. These are compounds containing a phenylpiperidine skeleton, which consists of a piperidine bound to a phenyl group, classified under the direct parent group Phenylpiperidines. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Piperidines class, specifically within the Phenylpiperidines subclass.

Categories:

Gilteritinib is categorized under the following therapeutic classes: Amines, Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, BCRP/ABCG2 Inhibitors, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A4 Substrates (strength unknown), Cytochrome P-450 Substrates, Kinase Inhibitor, MATE 1 Inhibitors, MATE inhibitors, Moderate Risk QTc-Prolonging Agents, OCT1 inhibitors, P-glycoprotein substrates, Protein Kinase Inhibitors, QTc Prolonging Agents, Tyrosine Kinase Inhibitors. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Gilteritinib include:

• Water Solubility:<1 mg/mL
• Boiling Point: 696 ºC at 760 mm Hg
• logP: 4.35