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Calaspargase pegol API Manufacturers & Suppliers

General Description:

Calaspargase pegol, identified by CAS number 941577-06-6, is a notable compound with significant therapeutic applications. Asparaginase is an important agent used to treat acute lymphoblastic leukemia (ALL) . Asparagine is incorporated into most proteins, and the synthesis of proteins is stopped when asparagine is absent, which inhibits RNA and DNA synthesis, resulting in a halt in cellular proliferation. This forms the basis of asparaginase treatment in ALL , , . Calaspargase pegol, also known as _asparlas_, is an asparagine specific enzyme which is indicated as a part of a multi-agent chemotherapy regimen for the treatment of ALL . The asparagine specific enzyme is derived from Escherichia coli, as a conjugate of L-asparaginase (L-asparagine amidohydrolase) and monomethoxypolyethylene glycol (mPEG) with a succinimidyl carbonate (SC) linker to create a stable molecule which increases the half-life and decreases the dosing frequency , . Calaspargase pegol, by _Shire_ pharmaceuticals, was approved by the FDA on December 20, 2018 for acute lymphoblastic anemia (ALL) .

Indications:

This drug is primarily indicated for: This drug is is an asparagine specific enzyme indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia in pediatric and young adult patients age 1 month to 21 years . The pharmacokinetics of calaspargase pegol were examined when given in combination with multiagent chemotherapy in 124 patients with B-cell lineage ALL . The FDA approval of this drug was based on the achievement and maintenance of nadir serum asparaginase activity above the level of 0.1 U/mL when administering calaspargase, 2500 U/m2 intravenously, at 3-week intervals. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Absorption:

The absorption characteristics of Calaspargase pegol are crucial for its therapeutic efficacy: Mean Tmax (1 h): 1.7 . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Calaspargase pegol is an important consideration for its dosing schedule: 16.1 days. This determines the duration of action and helps in formulating effective dosing regimens.

Volume of Distribution:

Calaspargase pegol is distributed throughout the body with a volume of distribution of: Vss (L): 2.96. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Calaspargase pegol is a critical factor in determining its safe and effective dosage: 0.147 L/day. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Calaspargase pegol exerts its therapeutic effects through: The effect of this drug is believed to occur by selective killing of leukemic cells due to depletion of plasma L-asparagine. Leukemic cells with low expression of asparagine synthetase are less capable of producing L-asparagine, and therefore rely on exogenous L-asparagine for survival . When asparagine is depleted, tumor cells cannot proliferate . During remission induction, one dose of SC-PEG (2500 IU/m2) results in a sustained therapeutic serum asparaginase activity (SAA) without excessive toxicity or marked differences in the proportion of patients with low end-induction minimum residual disease (MRD) . Pharmacodynamic (PD) response was studied through measurement of plasma and cerebrospinal fluid (CSF) asparagine concentrations with an LC-MS/MS assay (liquid chromatography–mass spectrometry). Asparagine concentration in plasma was sustained below the assay limit of quantification for more than 18 days after one dose of calaspargase pegol, 2,500 U/m2, during the induction phase of treatment. Average cerebrospinal asparagine concentrations decreased from a pretreatment concentration of 0.8 μg/mL (N=10) to 0.2 μg/mL on Day 4 (N=37) and stayed decreased at 0.2 μg/mL (N=35) 25 days after the administration of one of 2,500 U/m2 in the induction phase . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Calaspargase pegol functions by: L-asparaginase (the main component of this drug) is an enzyme that catalyzes the conversion of the amino acid L-asparagine into both aspartic acid and ammonia , . This process depletes malignant cells of their required asparagine. The depletion of asparagine then blocks protein synthesis and tumor cell proliferation, especially in the G1 phase of the cell cycle. As a result, tumor cell death occurs. Asparagine is important in protein synthesis in acute lymphoblastic leukemia (ALL) cells which, unlike normal cells, cannot produce this amino acid due to lack of the enzyme _asparagine synthase_ , . Pegylation decreases enzyme antigenicity and increases its half-life. Succinimidyl carbamate (SC) is used as a PEG linker to facilitate attachment to asparaginase and enhances the stability of the formulation , . SC-PEG urethane linkages formed with lysine groups are more hydrolytically stable . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Calaspargase pegol is categorized under the following therapeutic classes: Alcohols, Amidohydrolases, Asparagine-specific Enzyme, Compounds used in a research, industrial, or household setting, Enzymes, Enzymes and Coenzymes, Ethylene Glycols, Glycols, Hydrolases, Macromolecular Substances, Polymers. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.