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General Description:

Alpelisib, identified by CAS number 1217486-61-7, is a notable compound with significant therapeutic applications. Alpelisib is a phosphatidylinositol 3-kinase (PI3K) inhibitor with potent antitumor activity. It works by selectively inhibiting class I PI3K p110α , which is the catalytic subunit of PI3K, a lipid kinase that plays a role in various biological processes, including proliferation, survival, differentiation, and metabolism. Alpelisib was designed to target this enzyme that appears to be mutated at a rate of nearly 30% in human cancers, leading to hyperactivation. There are several isoform-specific PI3K inhibitors that are under clinical development or currently approved, such as used for chronic lymphocytic leukemia (CLL). Approved by the FDA in May 2019, alpelisib is the first approved PI3K inhibitor indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer in combination with for postmenopausal women and male patients. To initiate alpelisib therapy, it is required that the presence of a PIK3CA mutation in the tissue and/or liquid biopsy sample collection should be confirmed via FDA-approved diagnostic tests. Alpelisib is marketed under the trade name Piqray and is available as oral tablets. Studies evaluating the therapeutic effectiveness of alpelisib in other cancers, such as ovarian cancer and colorectal cancer , are under ongoing investigations. Alpelisib was granted FDA approval on 24 May 2019. In April 2022, the FDA granted the use of alpelisib in the treatment of PIK3CA-Related Overgrowth Spectrum (PROS) in adults and children who require systemic therapy.

Indications:

This drug is primarily indicated for: Alpelisib is indicated in combination with fulvestrant to treat postmenopausal women, and men, with advanced or metastatic breast cancer. This cancer must be hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, and PIK3CA­ mutated. The cancer must be detected by an FDA-approved test following progression on or after an endocrine-based regimen. Alpelisib is also used to treat adult and pediatric patients two years of age and older with severe manifestations of PIK3CA-Related Overgrowth Spectrum (PROS) who require systemic therapy. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Alpelisib undergoes metabolic processing primarily in: Alpelisib is metabolized by hydrolysis reactions to form the primary metabolite. It is also metabolized by CYP3A4. The full metabolism of Alpelisib has yet to be determined but a series of reactions have been proposed. The main metabolic reaction is the substitution of an amine group on alpelisib for a hydroxyl group to form a metabolite known as M4 or BZG791. Alpelisib can also be glucuronidated to form the M1 and M12 metabolites. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Alpelisib are crucial for its therapeutic efficacy: Alpelisib reached a peak concentration in plasma of 1320±912ng/mL after 2 hours. Alpelisib has an AUC_last of 11,100±3760h ng/mL and an AUC_INF of 11,100±3770h ng/mL. A large, high fat meal increases the AUC by 73% and C_max by 84% while a small, low fat meal increases the AUC by 77% and C_max by 145%. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Alpelisib is an important consideration for its dosing schedule: The mean half life of alprelisib is 8 to 9 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Alpelisib exhibits a strong affinity for binding with plasma proteins: Alpelisib is 89% protein bound. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Alpelisib from the body primarily occurs through: 36% of an oral dose is eliminated as unchanged drug in the feces and 32% as the primary metabolite BZG791 in the feces. About 2% of an oral dose is eliminated in the urine as unchanged drug and 7.1% as the primary metabolite BZG791. In total 81% of an oral dose is eliminated in the feces and 14% is eliminated in the urine. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Alpelisib is distributed throughout the body with a volume of distribution of: The apparent volume of distribution at steady state is 114L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Alpelisib is a critical factor in determining its safe and effective dosage: The mean apparent oral clearance was 39.0L/h. The predicted clearance is 9.2L/hr under fed conditions. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Alpelisib exerts its therapeutic effects through: Alpelisib does not prolong the QTcF interval. Patients taking alpelisib experience a dose dependent benefit from treatment with a 51% advantage of a 200mg daily dose over a 100mg dose and a 22% advantage of 300mg once daily over 150mg twice daily. This suggests patients requiring a lower dose may benefit from twice daily dosing. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Alpelisib functions by: Phosphatidylinositol-3-kinase-α (PI3Kα) is responsible for cell proliferation in response to growth factor-tyrosine kinase pathway activation. In some cancers PI3Kα's p110α catalytic subunit is mutated making it hyperactive. Alpelisib inhibits (PI3K), with the highest specificity for PI3Kα. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Alpelisib belongs to the class of organic compounds known as proline and derivatives. These are compounds containing proline or a derivative thereof resulting from reaction of proline at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom, classified under the direct parent group Proline and derivatives. This compound is a part of the Organic compounds, falling under the Organic acids and derivatives superclass, and categorized within the Carboxylic acids and derivatives class, specifically within the Amino acids, peptides, and analogues subclass.

Categories:

Alpelisib is categorized under the following therapeutic classes: Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, BCRP/ABCG2 Inhibitors, BCRP/ABCG2 Substrates, Breast Neoplasms, Cytochrome P-450 CYP2B6 Inducers, Cytochrome P-450 CYP2B6 Inducers (moderate), Cytochrome P-450 CYP2C19 Inhibitors, Cytochrome P-450 CYP2C19 inhibitors (strength unknown), Cytochrome P-450 CYP2C8 Inhibitors, Cytochrome P-450 CYP2C8 Inhibitors (strength unknown), Cytochrome P-450 CYP2C9 Inducers, Cytochrome P-450 CYP2C9 Inducers (moderate), Cytochrome P-450 CYP2C9 Inducers (strength unknown), Cytochrome P-450 CYP3A Inducers, Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Inducers, Cytochrome P-450 CYP3A4 Inducers (weak), Cytochrome P-450 CYP3A4 Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors (weak), Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A4 Substrates (strength unknown), Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index, Cytochrome P-450 Enzyme Inducers, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, Kinase Inhibitor, Narrow Therapeutic Index Drugs, P-glycoprotein inhibitors, Phosphatidylinositol 3-Kinases, antagonists & inhibitors, Phosphatidylinositol-3-kinase (Pi3K) inhibitors, Protein Kinase Inhibitors, Sulfur Compounds. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.