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General Description:

Duvelisib, identified by CAS number 1201438-56-3, is a notable compound with significant therapeutic applications. Duvelisib, also known as IPI-145 and INK-1197, is a small-molecule inhibitor of phosphoinositide-3 kinases that was designed initially to prove that simultaneous inhibition of the isoforms delta and gamma can produce a broad adaptative and innate immune cell inhibitory activity. All the work around duvelisib showed that this agent is a potent inhibitor of both forms. Duvelisib was developed by Verastem, Inc and FDA approved on September 24, 2018.

Indications:

This drug is primarily indicated for: Duvelisib is indicated for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adult patients who have trialed at least two prior therapies. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Duvelisib undergoes metabolic processing primarily in: Duvelesib is mainly metabolized by CYP3A4. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Duvelisib are crucial for its therapeutic efficacy: Duvelisib is rapidly absorbed and its peak plasma concentration is reached 1-2 hours after initial administration with a bioavailability of 42% and with a minimal accumulation whose rate ranges between 1.5 and 2.9. The maximal plasma concentration is reported to range in between 471 to 3294 ng/ml with a systemic exposure ranging from 2001 to 19059 ng.h/ml. Changes in the administered dose produce correspondent changes in all absorption parameters indicating a dose-response profile. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Duvelisib is an important consideration for its dosing schedule: The reported half-life of duvelisib is in the range of 5.2 to 10.9 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Duvelisib exhibits a strong affinity for binding with plasma proteins: The protein binding of duvelisib is greater than 98% and this level is not dependent on serum concentration. It is reported that duvelisib is a substrate of P-gp and BCRP. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Duvelisib from the body primarily occurs through: Duvelisib is eliminated after 3.5-9.5 hours when administered as a single dose and after 6.5-11.7 hours when given in multiple doses. From the administered dose, 79% os excreted in feces and 14% in urine. About 10% of the total administered dose is secreted unchanged. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Duvelisib is distributed throughout the body with a volume of distribution of: The volume of distribution of duvelisib ranges from 26 to 102 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Duvelisib is a critical factor in determining its safe and effective dosage: Duvelisib clearance rate is reported to be in the range of 3.6 to 11.2 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Duvelisib exerts its therapeutic effects through: Preclinical data showed that duvelisib presents cytotoxic actions at micromolar doses and antagonizes the activation of downstream signaling even in the presence of the mutation BTK C481S, which allows for the treatment of patients resistant to ibrutinib. In clinical trials, duvelisib was compared to ofatumumab in patients with chronic lymphocytic leukemia or small lymphocytic leukemia. This trials reported a median progression-free survival of 16.4 months and an overall response rate of 78% which were almost 2-fold what it was reported for ofatumumab. In clinical trials of follicular lymphoma, duvelisib presented and overall response rate of 42% from which almost all the patients observed a partial response. Of the responding patients, 43% maintained the response for at least 6 months and 17% for at least 12 months. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Duvelisib functions by: Duvelisib acts as a strong reversible inhibitor of the isoform gamma and delta of the phosphoinositide3-kinase (PI3K). PI3K plays a very important role in innate and adaptative immunity and the inhibition of the form delta and gamma has been very important for the suppression of immunity. The activity of PI3K gamma and delta is restricted to hematopoietic cells and it is necessary for normal B cell development. In lymphomas, the activation of PI3K is enlarged to promote unlimited growth and survival. Hence, inhibition of PI3K can provide an inhibition of the signaling from BCR, inhibition of a cytokine signaling from the microenvironment and enhancement of anti-tumor immunity. The specific mechanism of this PI3K inhibitors are further described as follows: -BCR activates signaling pathways after antigen engagement and it is also critical for the physiologic life of the lymphocytes and neoplastic lymphomas. In CLL, BCR reacts to auto- and exo-antigens to promote clonal expansion. This sustained presence of BCR activates delta PI3K producing a pro-survival pathway of the neoplastic cells which already present a higher activity of PI3K. Thus, the blockade of PI3K will limit the activity of BCR and the driven physiology of the lymphoma. -The inhibition of PI3K can also inhibit paracrine and autocrine pro-survival signals mediated by adhesion molecules, chemokines and soluble factors. This activity is attained due to the fact that several downstream signals convey on PI3K. -It has been reported that inactivation of PI3K produces a significant resistance to tumorigenesis. This data suggests that inhibition of PI3K can facilitate recognition and elimination of tumor cells. In summary, duvelisib inhibits the isoform delta of PI3K which is necessary for cell proliferation and survival and the isoform gamma which is critical for cytokine signaling and the pro-inflammatory response. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Duvelisib belongs to the class of organic compounds known as isoquinolones and derivatives. These are aromatic polycyclic compounds containing a ketone bearing isoquinoline moiety, classified under the direct parent group Isoquinolones and derivatives. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Isoquinolines and derivatives class, specifically within the Isoquinolones and derivatives subclass.

Categories:

Duvelisib is categorized under the following therapeutic classes: Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, BCRP/ABCG2 Substrates, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A4 Substrates (strength unknown), Cytochrome P-450 Substrates, Heterocyclic Compounds, Fused-Ring, Kinase Inhibitor, P-glycoprotein substrates, Phosphatidylinositol 3-Kinases, antagonists & inhibitors, Phosphatidylinositol-3-kinase (Pi3K) inhibitors, Protein 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 Duvelisib include:

• Water Solubility:<1 mg/ml
• Melting Point: >190 ºC
• logP: 4.55