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General Description:

Copanlisib, identified by CAS number 1032568-63-0, is a notable compound with significant therapeutic applications. Copanlisib is a selective pan-Class I phosphoinositide 3-kinase (PI3K/Phosphatidylinositol-4,5-bisphosphate 3-kinase/phosphatidylinositide 3-kinase) inhibitor that was first developed by Bayer Healthcare Pharmaceuticals, Inc. The drug targets the enzyme that plays a role in regulating cell growth and survival. Copanlisib was granted accelerated approval on September 14, 2017 under the market name Aliqopa for the treatment of adult patients with relapsed follicular lymphoma and a treatment history of at least two prior systemic therapies. Follicular lymphoma is a slow-growing type of non-Hodgkin lymphoma that is caused by unregulated proliferation and growth of lymphocytes. The active ingredient in Aliquopa intravenous therapy is copanlisib dihydrochloride.

Indications:

This drug is primarily indicated for: Indicated for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Copanlisib undergoes metabolic processing primarily in: Approximately >90% of copanlisib metabolism is mediated by CYP3A and less than 10% of the drug is metabolized by CYP1A1. The main detectable metabolite is M-1 that retains a comparable pharamcological activity to the parent drug against PI3Kα and PI3Kβ . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Copanlisib are crucial for its therapeutic efficacy: The plasma levels of copanlisib increases in a dose-proportional manner with linear pharmacokinetic properties and no time dependency. Following a steady state exposure at 0.8 mg/kg, the mean peak plasma concentration (Cmax) of copanlisib is 463 ng/mL with the range of 105 to 1670 ng/mL . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Copanlisib is an important consideration for its dosing schedule: The geometric mean terminal elimination half-life of copanlisib is 39.1 (range: 14.6 to 82.4; SD: 15.0) hours . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Copanlisib exhibits a strong affinity for binding with plasma proteins: The *in vitro* human plasma protein binding of copanlisib is 84.2%, with albumin being the main binding protein . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Copanlisib from the body primarily occurs through: Copanlisib is excreted approximately 50% as unchanged compound and 50% as metabolites in humans. After a single intravenously-administered dose of 12mg radiolableled drug, approximately 64% of the dose is excreted in feces and 22% is excreted in urine within 20 to 34 days. Unchanged copanlisib represented approximately 30% of the administered dose in feces and 15% in urine. Metabolites resulting from CYP450-mediated oxidation metabolism accounted for 41% of the administered dose . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Copanlisib is distributed throughout the body with a volume of distribution of: The *in vitro* mean blood-to-plasma ratio is 1.7 (range: 1.5 to 2.1). The geometric mean volume of distribution is 871 (range: 423 to 2150; SD: 479) L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Copanlisib is a critical factor in determining its safe and effective dosage: The geometric mean clearance is 17.9 (range: 7.3 to 51.4; SD: 8.5) L/hr . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Copanlisib exerts its therapeutic effects through: Copanlisib has demonstrated potent anti-tumor and pro-apoptotic activity in various tumor cell lines and xenograft models . In clinical trials, 59 percent of patients receiving copanlisib achieved complete or partial shrinkage of their tumors after a median of 12.2 months . Higher systemic levels of copanlisib is associated with elevated plasma glucose levels. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Copanlisib functions by: Follicular lymphoma is a B-cell lymphoma that is one of the most common type of non-Hodgkin lymphoma (NHL). It involves unregulated growth and proliferation of lymphocytes that eventually may travel to other organs including the lymph nodes, spleen, and the bone marrow, to form tumors. The phosphatidylinositol 3-kinase (PI3K)-mediated pathway is involved in promoting cell survival proliferation and differentiation however abberant activation of this pathway may lead to tumorigenesis . Copanlisib mediates an inhibitory action on p110α and p110δ isoforms of phosphatidylinositol-3-kinase (PI3K) expressed in malignant B cells. It induces tumor cell death via apoptosis and inhibits the proliferation of primary malignant B cell lines . Copanlisib inhibits several key cell-signaling pathways, including B-cell receptor (BCR) signaling, CXCR12 mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Copanlisib belongs to the class of organic compounds known as quinazolinamines. These are heterocyclic aromatic compounds containing a quianazoline moiety substituted by one or more amine groups, classified under the direct parent group Quinazolinamines. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Diazanaphthalenes class, specifically within the Benzodiazines subclass.

Categories:

Copanlisib 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 with a Narrow Therapeutic Index, Cytochrome P-450 CYP3A5 Substrates, Cytochrome P-450 CYP3A5 Substrates with a Narrow Therapeutic Index, Cytochrome P-450 CYP3A7 Substrates, Cytochrome P-450 CYP3A7 Substrates with a Narrow Therapeutic Index, Cytochrome P-450 Substrates, Heterocyclic Compounds, Fused-Ring, Kinase Inhibitor, MATE 2 Inhibitors, MATE inhibitors, Narrow Therapeutic Index Drugs, P-glycoprotein substrates, P-glycoprotein substrates with a Narrow Therapeutic Index, Phosphatidylinositol-3-kinase (Pi3K) inhibitors, Protein Kinase Inhibitors. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.