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Calaspargase pegol, カラスパルガーゼペゴル

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LPNITILATG GTIAGGGDSA TKSNYTAGKV GVENLVNAVP QLKDIANVKG EQVVNIGSQD
MNDDVWLTLA KKINTDCDKT DGFVITHGTD TMEETAYFLD LTVKCDKPVV MVGAMRPSTS
MSADGPFNLY NAVVTAADKA SANRGVLVVM NDTVLDGRDV TKTNTTDVAT FKSVNYGPLG
YIHNGKIDYQ RTPARKHTSD TPFDVSKLNE LPKVGIVYNY ANASDLPAKA LVDAGYDGIV
SAGVGNGNLY KTVFDTLATA AKNGTAVVRS SRVPTGATTQ DAEVDDAKYG FVASGTLNPQ
KARVLLQLAL TQTKDPQQIQ QIFNQY
(tetramer; disulfide bridge 77-105, 77′-105′, 77”-105”, 77”’-105”’)

Image result for Calaspargase pegol

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Calaspargase pegol

Molecular Formula, C1516-H2423-N415-O492-S8 (peptide monomer), Molecular Weight, 10261.2163

APPROVED, Asparlas, FDA 2018/12/20

CAS 941577-06-6

UNII T9FVH03HMZ

カラスパルガーゼペゴル;

(27-Alanine,64-aspartic acid,252-threonine,263-asparagine)-L-asparaginase 2 (EC 3.5.1.1, L-asparagineamidohydrolase II) Escherichia coli (strain K12) tetramer alpha4, carbamates with alpha-carboxy-omega-methoxypoly(oxyethylene)

Asparaginase (Escherichia coli isoenzyme II), conjugate with alpha-(((2,5-dioxo-1-pyrrolidinyl)oxy)carbonyl)-omega-methoxypoly(oxy-1,2-ethanediyl)

List Acronyms
Peptide
  • Calaspargase pegol
  • calaspargase pegol-mknl
  • EZN-2285
  • Used to treat acute lymphoblastic leukemia., Antineoplastic
  • BAX-2303
    SC-PEG E. Coli L-asparaginase
    SHP-663

Calaspargase pegol-mknl (trade name Asparlas) is a drug for the treatment of acute lymphoblastic leukemia (ALL). It is approved by the Food and Drug Administration for use in the United States as a component of a multi-agent chemotherapeutic regimen for ALL in pediatric and young adult patients aged 1 month to 21 years.[1]

Calaspargase pegol was first approved in 2018 in the U.S. as part of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia.

In 2008, orphan drug designation was assigned in the E.U.

Calaspargase pegol is an engineered protein consisting of the E. coli-derived enzyme L-asparaginase II conjugated with succinimidyl carbonate monomethoxypolyethylene glycol (pegol).[2] The L-asparaginase portion hydrolyzes L-asparagine to L-aspartic acid depriving the tumor cell of the L-asparagine it needs for survival.[2] The conjugation with the pegol group increases the half-life of the drug making it longer acting.

Asparaginase is an important agent used to treat acute lymphoblastic leukemia (ALL) [1]. 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 [1][2][6].

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 [3]. 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 [Label][1].

Calaspargase pegol, by Shire pharmaceuticals, was approved by the FDA on December 20, 2018 for acute lymphoblastic anemia (ALL) [3].

Indication

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 [Label].

The pharmacokinetics of calaspargase pegol were examined when given in combination with multiagent chemotherapy in 124 patients with B-cell lineage ALL [3]. 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.

Associated Conditions

Pharmacodynamics

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 [Label]. When asparagine is depleted, tumor cells cannot proliferate [6].

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) [5].

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 [Label].

Mechanism of action

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 [Label][2]. 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 [2][Label].

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 [4][1]. SC-PEG urethane linkages formed with lysine groups are more hydrolytically stable [2].

Toxicity

Pancreatitis, hepatotoxicity, hemorrhage, and thrombosis have been observed with calaspargase pegol use [Label].

Pancreatitis: Discontinue this drug in patients with pancreatitis, and monitor blood glucose.

Hepatotoxicity: Hepatic function should be tested regularly, and trough levels of this drug should be measured during the recovery phase of the drug cycle [Label].

Hemorrhage or Thrombosis: Discontinue this drug in serious or life-threatening hemorrhage or thrombosis. In cases of hemorrhage, identify the cause of hemorrhage and treat appropriately. Administer anticoagulant therapy as indicated in thrombotic events [Label].

A note on hypersensitivity:

Observe the patient for 1 hour after administration of calaspargase pegol for possible hypersensitivity [Label]. In cases of previous hypersensitivity to this drug, discontinue this drug immediately.

Lactation: Advise women not to breastfeed while taking this drug [Label].

Pregnancy: There are no available data on the use of calaspargase pegol in pregnant women to confirm a risk of drug-associated major birth defects and miscarriage. Published literature studies in pregnant animals suggest asparagine depletion can cause harm to the animal offspring. It is therefore advisable to inform women of childbearing age of this risk. The background risk of major birth defects and miscarriage for humans is unknown at this time [Label].

Pregnancy testing should occur before initiating treatment. Advise females of reproductive potential to avoid becoming pregnant while taking this drug. Females should use effective contraceptive methods, including a barrier methods, during treatment and for at least 3 months after the last dose. There is a risk for an interaction between calaspargase pegol and oral contraceptives. The concurrent use of this drug with oral contraceptives should be avoided. Other non-oral contraceptive methods should be used in women of childbearing potential [Label].

References
  1. Angiolillo AL, Schore RJ, Devidas M, Borowitz MJ, Carroll AJ, Gastier-Foster JM, Heerema NA, Keilani T, Lane AR, Loh ML, Reaman GH, Adamson PC, Wood B, Wood C, Zheng HW, Raetz EA, Winick NJ, Carroll WL, Hunger SP: Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children’s Oncology Group Study AALL07P4. J Clin Oncol. 2014 Dec 1;32(34):3874-82. doi: 10.1200/JCO.2014.55.5763. Epub 2014 Oct 27. [PubMed:25348002]
  2. Appel IM, Kazemier KM, Boos J, Lanvers C, Huijmans J, Veerman AJ, van Wering E, den Boer ML, Pieters R: Pharmacokinetic, pharmacodynamic and intracellular effects of PEG-asparaginase in newly diagnosed childhood acute lymphoblastic leukemia: results from a single agent window study. Leukemia. 2008 Sep;22(9):1665-79. doi: 10.1038/leu.2008.165. Epub 2008 Jun 26. [PubMed:18580955]
  3. Blood Journal: Randomized Study of Pegaspargase (SS-PEG) and Calaspargase Pegol (SPC-PEG) in Pediatric Patients with Newly Diagnosed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma: Results of DFCI ALL Consortium Protocol 11-001 [Link]

References

  1. ^ “FDA approves longer-acting calaspargase pegol-mknl for ALL” (Press release). Food and Drug Administration. December 20, 2018.
  2. Jump up to:a b “Calaspargase pegol-mknl”NCI Drug Dictionary. National Cancer Institute.

FDA label, Download(300 KB)

General References

  1. Angiolillo AL, Schore RJ, Devidas M, Borowitz MJ, Carroll AJ, Gastier-Foster JM, Heerema NA, Keilani T, Lane AR, Loh ML, Reaman GH, Adamson PC, Wood B, Wood C, Zheng HW, Raetz EA, Winick NJ, Carroll WL, Hunger SP: Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children’s Oncology Group Study AALL07P4. J Clin Oncol. 2014 Dec 1;32(34):3874-82. doi: 10.1200/JCO.2014.55.5763. Epub 2014 Oct 27. [PubMed:25348002]
  2. Appel IM, Kazemier KM, Boos J, Lanvers C, Huijmans J, Veerman AJ, van Wering E, den Boer ML, Pieters R: Pharmacokinetic, pharmacodynamic and intracellular effects of PEG-asparaginase in newly diagnosed childhood acute lymphoblastic leukemia: results from a single agent window study. Leukemia. 2008 Sep;22(9):1665-79. doi: 10.1038/leu.2008.165. Epub 2008 Jun 26. [PubMed:18580955]
  3. Asparlas Approval History [Link]
  4. NCI: Calaspargase Pegol [Link]
  5. Blood Journal: Randomized Study of Pegaspargase (SS-PEG) and Calaspargase Pegol (SPC-PEG) in Pediatric Patients with Newly Diagnosed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma: Results of DFCI ALL Consortium Protocol 11-001 [Link]
  6. Medsafe NZ: Erwinaze inj [File]
Calaspargase pegol-mknl
Clinical data
Trade names Asparlas
Synonyms EZN-2285
Legal status
Legal status
Identifiers
CAS Number
DrugBank
UNII
KEGG
ChEMBL

/////////////Calaspargase pegol, Peptide, FDA 2018, EZN-2285, カラスパルガーゼペゴル  , BAX-2303, SC-PEG E. Coli L-asparaginase , SHP-663, orphan drug

CC(C)C[C@@H](C(=O)O)NC(=O)OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOC.COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOC(=O)NCCCC[C@@H](C(=O)O)N

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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