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Mifamurtide

December 02, 2023

Mifamurtide (trade name Mepact, marketed by Takeda) is a drug against osteosarcoma, a kind of bone cancer mainly affecting children and young adults, which is lethal in over half of cases. The drug was approved in Europe in March 2009.

Mifamurtide
Clinical data
Trade namesMepact
License data
  • EU EMA: by INN
Pregnancy
category
  • not investigated
Routes of
administration		intravenous liposomal infusion over one hour
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityN/A
Elimination half-lifeminutes (in plasma)
18 hrs (terminal)
Identifiers
  • 2-[(N-{(2R)-[(2-acetamido-2,3-dideoxy-D-glucopyranos-3-yl)oxy]-propanoyl}-L-alanyl-D-isoglutaminyl-L-alanyl)amino]ethyl (2R)-2,3-bis(hexadecanoyloxy)propyl hydrogen phosphate
CAS Number
  • 83461-56-7 Y
    838853-48-8 (mifamurtide sodium · x H2O)
PubChem CID
  • 11672602
ChemSpider
  • 9847332 N
UNII
  • EQD2NNX741
KEGG
  • D06619 Y
Chemical and physical data
FormulaC59H109N6O19P
Molar mass1237.518 g·mol−1
3D model (JSmol)
  • Interactive image
  • CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCCNC(=O)[C@H](C)NC(=O)CC[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](C)O[C@H]1C(O)[C@@H](CO)O[C@@H](O)[C@@H]1NC(C)=O)C(N)=O)OC(=O)CCCCCCCCCCCCCCC
  • InChI=1S/C59H109N6O19P/c1-7-9-11-13-15-17-19-21-23-25-27-29-31-33-50(69)79-40-46(83-51(70)34-32-30-28-26-24-22-20-18-16-14-12-10-8-2)41-81-85(77,78)80-38-37-61-56(73)42(3)62-49(68)36-35-47(55(60)72)65-57(74)43(4)63-58(75)44(5)82-54-52(64-45(6)67)59(76)84-48(39-66)53(54)71/h42-44,46-48,52-54,59,66,71,76H,7-41H2,1-6H3,(H2,60,72)(H,61,73)(H,62,68)(H,63,75)(H,64,67)(H,65,74)(H,77,78)/t42-,43-,44+,46+,47+,48+,52+,53+,54+,59?/m0/s1 N
  • Key:JMUHBNWAORSSBD-WKYWBUFDSA-N N
 NY (what is this?)  (verify)

Medical uses edit

Mifamurtide is indicated for the treatment of high-grade, nonmetastasizing, resectable osteosarcoma following complete surgical removal in children, adolescents, and young adults, aged two to 30 years.[1][2][3] Osteosarcoma is diagnosed in about 1,000 individuals in Europe and the USA per year, most under the age of 30.[4] The drug is used in combination with postoperative, multiagent chemotherapy to kill remaining cancer cells and improve a patient's chance of overall survival.[2]

In a phase-III clinical trial in about 800 newly diagnosed osteosarcoma patients, mifamurtide was combined with the chemotherapeutic agents doxorubicin and methotrexate, with or without cisplatin and ifosfamide. The mortality could be lowered by 30% versus chemotherapy plus placebo. Six years after the treatment, 78% of patients were still alive. This equals an absolute risk reduction of 8% .[1]

Adverse effects edit

In a clinical study, mifamurtide was given to 332 subjects (half of whom were under age of 16) and most side effects were found to be mild to moderate in nature. Most patients experience fewer adverse events with subsequent administration.[5][6] Common side effects include fever (about 90%), vomiting, fatigue and tachycardia (about 50%), infections, anaemia, anorexia, headache, diarrhoea and constipation (>10%).[1][7]

Interactions edit

Consequently, the combination of mifamurtide with these types of drugs is contraindicated. However, mifamurtide can be coadministered with low doses of NSAIDs. No evidence suggests mifamurtide interacts with the studied chemotherapeutics, or with the cytochrome P450 system.[8]

Pharmacology edit

Mechanism of action edit

Mifamurtide is a fully synthetic derivative of muramyl dipeptide (MDP), the smallest naturally occurring immune stimulatory component of cell walls from Mycobacterium species. It has similar immunostimulatory effects as natural MDP with the advantage of a longer half-life in plasma.

NOD2 is a pattern recognition receptor which is found in several kinds of white blood cells, mainly monocytes and macrophages. It recognises muramyl dipeptide, a component of the cell wall of bacteria. Mifamurtide simulates a bacterial infection by binding to NOD2, activating white cells. This results in an increased production of TNF-α, interleukin 1, interleukin 6, interleukin 8, interleukin 12, and other cytokines, as well as ICAM-1. The activated white cells attack cancer cells, but not, at least in vitro, other cells.[9]

Pharmacokinetics edit

After application of the liposomal infusion, the drug is cleared from the plasma within minutes and is concentrated in lung, liver, spleen, nasopharynx, and thyroid. The terminal half-life is 18 hours. In patients receiving a second treatment after 11–12 weeks, no accumulation effects were observed.[10]

Chemistry edit

 
Scheme of a liposome formed by phospholipids in an aqueous solution

Mifamurtide is muramyl tripeptide phosphatidylethanolamine (MTP-PE), a synthetic analogue of muramyl dipeptide. The side chains of the molecule give it a longer elimination half-life than the natural substance. The substance is applied encapsulated into liposomes (L-MTP-PE). Being a phospholipid, it accumulates in the lipid bilayer of the liposomes in the infusion.[11]

Synthesis edit

One method of synthesis (shown first) is based on N,N'-dicyclohexylcarbodiimide (DCC) assisted esterification of N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine with N-hydroxysuccinimide, followed by a condensation with 2-aminoethyl-2,3-dipalmitoylglycerylphosphoric acid in triethylamine (Et3N).[12] A different approach (shown second) uses N-acetylmuramyl-L-alanyl-D-isoglutamine, hydroxysuccinimide and alanyl-2-aminoethyl-2,3-dipalmitoylglycerylphosphoric acid;[13] that is, the alanine is introduced in the second step instead of the first.

   

History edit

The drug was invented by Ciba-Geigy (now Novartis) in the early 1980s and sold to Jenner Biotherapies in the 1990s. In 2003, IDM Pharma bought the rights and developed it further.[1] IDM Pharma was acquired by Takeda along with mifamurtide in June 2009.[14]

Mifamurtide had already been granted orphan drug status by the U.S. Food and Drug Administration (FDA) in 2001, and the European Medicines Agency (EMA) followed in 2004. It was approved in the 27 European Union member states plus Iceland, Liechtenstein, and Norway by a centralized marketing authorization in March 2009. The drug was denied approval by the FDA in 2007.[15][16] Mifamurtide has been licensed by the EMA since March, 2009.[17]

References edit

  1. ^ a b c d "Mifamurtide: CGP 19835, CGP 19835A, L-MTP-PE, liposomal MTP-PE, MLV 19835A, MTP-PE, muramyltripeptide phosphatidylethanolamine". Drugs in R&D. 9 (2): 131–5. 2008. doi:10.2165/00126839-200809020-00007. PMID 18298131.
  2. ^ a b EMA (2009-03-06). "Mepact: Product Information. Annex I: Summary of Product Characteristics" (PDF). p. 2. Retrieved 2009-11-12.[dead link]
  3. ^ EMA (2009-05-06). "Mepact: European Public Assessment Report. Summary for the public" (PDF). p. 1. Retrieved 2016-10-06.
  4. ^ Meyers PA (August 2009). "Muramyl tripeptide (mifamurtide) for the treatment of osteosarcoma". Expert Review of Anticancer Therapy. 9 (8): 1035–49. doi:10.1586/era.09.69. PMID 19671023. S2CID 29512704.
  5. ^ Meyers PA, Schwartz CL, Krailo MD, Healey JH, Bernstein ML, Betcher D, et al. (February 2008). "Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival--a report from the Children's Oncology Group". Journal of Clinical Oncology. 26 (4): 633–8. doi:10.1200/JCO.2008.14.0095. PMID 18235123.
  6. ^ Meyers PA, Schwartz CL, Krailo M, Kleinerman ES, Betcher D, Bernstein ML, et al. (March 2005). "Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate". Journal of Clinical Oncology. 23 (9): 2004–11. doi:10.1200/JCO.2005.06.031. PMID 15774791.
  7. ^ (EMA & 2009-03-06, pp. 5–7)
  8. ^ (EMA & 2009-03-06, p. 4)
  9. ^ (EMA & 2009-03-06, pp. 7–8)
  10. ^ (EMA & 2009-03-06, p. 8)
  11. ^ Fidler IJ, Sone S, Fogler WE, Smith D, Braun DG, Tarcsay L, Gisler RH, Schroit AJ (1982). "Efficacy of liposomes containing a lipophilic muramyl dipeptide derivative for activating the tumoricidal properties of alveolar macrophages in vivo". Journal of Immunotherapy. 1 (1): 43–55.
  12. ^ Prous J, Castaner J (1989). "ENV 2-3/MTP-PE". Drugs of the Future. 14 (3): 220. doi:10.1358/dof.1989.014.03.85085.
  13. ^ Brundish DE, Wade R (1985). "Synthesis of N-[2-3H]acetyl-D-muramyl-L-alanyl-D-iso-glutaminyl-L-alanyl-2-(1',2'-dipalmitoyl-sn-glycero-3'-phosphoryl)ethylamide of high specific radioactivity". J Label Compd Radiopharm. 22 (1): 29–35. doi:10.1002/jlcr.2580220105.
  14. ^ "First Treatment to Improve Survival in 20 Years Now Available for Patients With Osteosarcoma (Bone Cancer)". Takeda. November 2009. Retrieved 23 March 2010.
  15. ^ "IDM Pharma's MEPACT (Mifamurtide, L-MTP-PE) Receives Approval in Europe for Treatment of Patients with Non-Metastatic, Resectable Osteosarcoma". PR Newswire. 2009-03-09. Retrieved 2009-11-12.
  16. ^ "IDM Pharma receives not approvable letter for Mifamurtide for treatment of osteosarcoma". The Medical News. 2007-08-28. Retrieved 2009-11-12.
  17. ^ Mepact for Healthcare Professionals, retrieved 2009-11-12

December 02, 2023
mifamurtide, trade, name, mepact, marketed, takeda, drug, against, osteosarcoma, kind, bone, cancer, mainly, affecting, children, young, adults, which, lethal, over, half, cases, drug, approved, europe, march, 2009, clinical, datatrade, namesmepactlicense, dat. Mifamurtide trade name Mepact marketed by Takeda is a drug against osteosarcoma a kind of bone cancer mainly affecting children and young adults which is lethal in over half of cases The drug was approved in Europe in March 2009 MifamurtideClinical dataTrade namesMepactLicense dataEU EMA by INNPregnancycategorynot investigatedRoutes ofadministrationintravenous liposomal infusion over one hourATC codeL03AX15 WHO Legal statusLegal statusIn general Prescription only Pharmacokinetic dataBioavailabilityN AElimination half lifeminutes in plasma 18 hrs terminal IdentifiersIUPAC name 2 N 2R 2 acetamido 2 3 dideoxy D glucopyranos 3 yl oxy propanoyl L alanyl D isoglutaminyl L alanyl amino ethyl 2R 2 3 bis hexadecanoyloxy propyl hydrogen phosphateCAS Number83461 56 7 Y 838853 48 8 mifamurtide sodium x H2O PubChem CID11672602ChemSpider9847332 NUNIIEQD2NNX741KEGGD06619 YChemical and physical dataFormulaC 59H 109N 6O 19PMolar mass1237 518 g mol 13D model JSmol Interactive imageSMILES CCCCCCCCCCCCCCCC O OCC COP O O OCCNC O C H C NC O CC C H NC O C H C NC O C H C O C H 1C O C H CO O C H O C H 1NC C O C N O OC O CCCCCCCCCCCCCCCInChI InChI 1S C59H109N6O19P c1 7 9 11 13 15 17 19 21 23 25 27 29 31 33 50 69 79 40 46 83 51 70 34 32 30 28 26 24 22 20 18 16 14 12 10 8 2 41 81 85 77 78 80 38 37 61 56 73 42 3 62 49 68 36 35 47 55 60 72 65 57 74 43 4 63 58 75 44 5 82 54 52 64 45 6 67 59 76 84 48 39 66 53 54 71 h42 44 46 48 52 54 59 66 71 76H 7 41H2 1 6H3 H2 60 72 H 61 73 H 62 68 H 63 75 H 64 67 H 65 74 H 77 78 t42 43 44 46 47 48 52 53 54 59 m0 s1 NKey JMUHBNWAORSSBD WKYWBUFDSA N N N Y what is this verify Contents 1 Medical uses 2 Adverse effects 3 Interactions 4 Pharmacology 4 1 Mechanism of action 4 2 Pharmacokinetics 5 Chemistry 5 1 Synthesis 6 History 7 ReferencesMedical uses editMifamurtide is indicated for the treatment of high grade nonmetastasizing resectable osteosarcoma following complete surgical removal in children adolescents and young adults aged two to 30 years 1 2 3 Osteosarcoma is diagnosed in about 1 000 individuals in Europe and the USA per year most under the age of 30 4 The drug is used in combination with postoperative multiagent chemotherapy to kill remaining cancer cells and improve a patient s chance of overall survival 2 In a phase III clinical trial in about 800 newly diagnosed osteosarcoma patients mifamurtide was combined with the chemotherapeutic agents doxorubicin and methotrexate with or without cisplatin and ifosfamide The mortality could be lowered by 30 versus chemotherapy plus placebo Six years after the treatment 78 of patients were still alive This equals an absolute risk reduction of 8 1 Adverse effects editIn a clinical study mifamurtide was given to 332 subjects half of whom were under age of 16 and most side effects were found to be mild to moderate in nature Most patients experience fewer adverse events with subsequent administration 5 6 Common side effects include fever about 90 vomiting fatigue and tachycardia about 50 infections anaemia anorexia headache diarrhoea and constipation gt 10 1 7 Interactions editTheoretical considerations suggest calcineurin inhibitors like ciclosporin and tacrolimus might interact with mifamurtide because of their effect on macrophages High dose NSAIDs block the mechanism of mifamurtide in vitro Consequently the combination of mifamurtide with these types of drugs is contraindicated However mifamurtide can be coadministered with low doses of NSAIDs No evidence suggests mifamurtide interacts with the studied chemotherapeutics or with the cytochrome P450 system 8 Pharmacology editMechanism of action edit Mifamurtide is a fully synthetic derivative of muramyl dipeptide MDP the smallest naturally occurring immune stimulatory component of cell walls from Mycobacterium species It has similar immunostimulatory effects as natural MDP with the advantage of a longer half life in plasma NOD2 is a pattern recognition receptor which is found in several kinds of white blood cells mainly monocytes and macrophages It recognises muramyl dipeptide a component of the cell wall of bacteria Mifamurtide simulates a bacterial infection by binding to NOD2 activating white cells This results in an increased production of TNF a interleukin 1 interleukin 6 interleukin 8 interleukin 12 and other cytokines as well as ICAM 1 The activated white cells attack cancer cells but not at least in vitro other cells 9 Pharmacokinetics edit After application of the liposomal infusion the drug is cleared from the plasma within minutes and is concentrated in lung liver spleen nasopharynx and thyroid The terminal half life is 18 hours In patients receiving a second treatment after 11 12 weeks no accumulation effects were observed 10 Chemistry edit nbsp Scheme of a liposome formed by phospholipids in an aqueous solutionMifamurtide is muramyl tripeptide phosphatidylethanolamine MTP PE a synthetic analogue of muramyl dipeptide The side chains of the molecule give it a longer elimination half life than the natural substance The substance is applied encapsulated into liposomes L MTP PE Being a phospholipid it accumulates in the lipid bilayer of the liposomes in the infusion 11 Synthesis edit One method of synthesis shown first is based on N N dicyclohexylcarbodiimide DCC assisted esterification of N acetylmuramyl L alanyl D isoglutaminyl L alanine with N hydroxysuccinimide followed by a condensation with 2 aminoethyl 2 3 dipalmitoylglycerylphosphoric acid in triethylamine Et3N 12 A different approach shown second uses N acetylmuramyl L alanyl D isoglutamine hydroxysuccinimide and alanyl 2 aminoethyl 2 3 dipalmitoylglycerylphosphoric acid 13 that is the alanine is introduced in the second step instead of the first nbsp nbsp History editThe drug was invented by Ciba Geigy now Novartis in the early 1980s and sold to Jenner Biotherapies in the 1990s In 2003 IDM Pharma bought the rights and developed it further 1 IDM Pharma was acquired by Takeda along with mifamurtide in June 2009 14 Mifamurtide had already been granted orphan drug status by the U S Food and Drug Administration FDA in 2001 and the European Medicines Agency EMA followed in 2004 It was approved in the 27 European Union member states plus Iceland Liechtenstein and Norway by a centralized marketing authorization in March 2009 The drug was denied approval by the FDA in 2007 15 16 Mifamurtide has been licensed by the EMA since March 2009 17 References edit a b c d Mifamurtide CGP 19835 CGP 19835A L MTP PE liposomal MTP PE MLV 19835A MTP PE muramyltripeptide phosphatidylethanolamine Drugs in R amp D 9 2 131 5 2008 doi 10 2165 00126839 200809020 00007 PMID 18298131 a b EMA 2009 03 06 Mepact Product Information Annex I Summary of Product Characteristics PDF p 2 Retrieved 2009 11 12 dead link EMA 2009 05 06 Mepact European Public Assessment Report Summary for the public PDF p 1 Retrieved 2016 10 06 Meyers PA August 2009 Muramyl tripeptide mifamurtide for the treatment of osteosarcoma Expert Review of Anticancer Therapy 9 8 1035 49 doi 10 1586 era 09 69 PMID 19671023 S2CID 29512704 Meyers PA Schwartz CL Krailo MD Healey JH Bernstein ML Betcher D et al February 2008 Osteosarcoma the addition of muramyl tripeptide to chemotherapy improves overall survival a report from the Children s Oncology Group Journal of Clinical Oncology 26 4 633 8 doi 10 1200 JCO 2008 14 0095 PMID 18235123 Meyers PA Schwartz CL Krailo M Kleinerman ES Betcher D Bernstein ML et al March 2005 Osteosarcoma a randomized prospective trial of the addition of ifosfamide and or muramyl tripeptide to cisplatin doxorubicin and high dose methotrexate Journal of Clinical Oncology 23 9 2004 11 doi 10 1200 JCO 2005 06 031 PMID 15774791 EMA amp 2009 03 06 pp 5 7 EMA amp 2009 03 06 p 4 EMA amp 2009 03 06 pp 7 8 EMA amp 2009 03 06 p 8 Fidler IJ Sone S Fogler WE Smith D Braun DG Tarcsay L Gisler RH Schroit AJ 1982 Efficacy of liposomes containing a lipophilic muramyl dipeptide derivative for activating the tumoricidal properties of alveolar macrophages in vivo Journal of Immunotherapy 1 1 43 55 Prous J Castaner J 1989 ENV 2 3 MTP PE Drugs of the Future 14 3 220 doi 10 1358 dof 1989 014 03 85085 Brundish DE Wade R 1985 Synthesis of N 2 3H acetyl D muramyl L alanyl D iso glutaminyl L alanyl 2 1 2 dipalmitoyl sn glycero 3 phosphoryl ethylamide of high specific radioactivity J Label Compd Radiopharm 22 1 29 35 doi 10 1002 jlcr 2580220105 First Treatment to Improve Survival in 20 Years Now Available for Patients With Osteosarcoma Bone Cancer Takeda November 2009 Retrieved 23 March 2010 IDM Pharma s MEPACT Mifamurtide L MTP PE Receives Approval in Europe for Treatment of Patients with Non Metastatic Resectable Osteosarcoma PR Newswire 2009 03 09 Retrieved 2009 11 12 IDM Pharma receives not approvable letter for Mifamurtide for treatment of osteosarcoma The Medical News 2007 08 28 Retrieved 2009 11 12 Mepact for Healthcare Professionals retrieved 2009 11 12 Retrieved from https en wikipedia org w index php title Mifamurtide amp oldid 1184087907, wikipedia, wiki, book, books, library,

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