Mifamurtide

Jump to navigation Jump to search
Mifamurtide
Clinical data
[[Regulation of therapeutic goods |Template:Engvar data]]
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
CAS Number
PubChem CID
UNII
KEGG
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC59H109N6O19P
Molar mass1237.499 g/mol
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

WikiDoc Resources for Mifamurtide

Articles

Most recent articles on Mifamurtide

Most cited articles on Mifamurtide

Review articles on Mifamurtide

Articles on Mifamurtide in N Eng J Med, Lancet, BMJ

Media

Powerpoint slides on Mifamurtide

Images of Mifamurtide

Photos of Mifamurtide

Podcasts & MP3s on Mifamurtide

Videos on Mifamurtide

Evidence Based Medicine

Cochrane Collaboration on Mifamurtide

Bandolier on Mifamurtide

TRIP on Mifamurtide

Clinical Trials

Ongoing Trials on Mifamurtide at Clinical Trials.gov

Trial results on Mifamurtide

Clinical Trials on Mifamurtide at Google

Guidelines / Policies / Govt

US National Guidelines Clearinghouse on Mifamurtide

NICE Guidance on Mifamurtide

NHS PRODIGY Guidance

FDA on Mifamurtide

CDC on Mifamurtide

Books

Books on Mifamurtide

News

Mifamurtide in the news

Be alerted to news on Mifamurtide

News trends on Mifamurtide

Commentary

Blogs on Mifamurtide

Definitions

Definitions of Mifamurtide

Patient Resources / Community

Patient resources on Mifamurtide

Discussion groups on Mifamurtide

Patient Handouts on Mifamurtide

Directions to Hospitals Treating Mifamurtide

Risk calculators and risk factors for Mifamurtide

Healthcare Provider Resources

Symptoms of Mifamurtide

Causes & Risk Factors for Mifamurtide

Diagnostic studies for Mifamurtide

Treatment of Mifamurtide

Continuing Medical Education (CME)

CME Programs on Mifamurtide

International

Mifamurtide en Espanol

Mifamurtide en Francais

Business

Mifamurtide in the Marketplace

Patents on Mifamurtide

Experimental / Informatics

List of terms related to Mifamurtide

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

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 about a third of cases. The drug was approved in Europe in March 2009.

History

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.[2]

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.[3][4] Mifamurtide has been licensed by the EMA since March, 2009.[5]

Indications

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][6][7] Osteosarcoma is diagnosed in about 1,000 individuals in Europe and the USA per year, most under the age of 30.[8] The drug is used in combination with postoperative, multiagent chemotherapy to kill remaining cancer cells and improve a patient's chance of overall survival.[6]

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

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.[9][10] Common side effects include fever (about 90%), vomiting, fatigue and tachycardia (about 50%), infections, anaemia, anorexia, headache, diarrhoea and constipation (>10%).[1][11]

Pharmacokinetics

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.[12]

Pharmacodynamics

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.[13]

Interactions

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.[14]

Chemistry

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.[15]

Synthesis

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).[16] A different approach (shown second) uses N-acetylmuramyl-L-alanyl-D-isoglutamine, hydroxysuccinimide and alanyl-2-aminoethyl-2,3-dipalmitoylglycerylphosphoric acid;[17] that is, the alanine is introduced in the second step instead of the first.

References

  1. 1.0 1.1 1.2 1.3 PMID 18298131 (PMID 18298131)
    Citation will be completed automatically in a few minutes. Jump the queue or expand by hand
  2. "First Treatment to Improve Survival in 20 Years Now Available for Patients With Osteosarcoma (Bone Cancer)". Takeda. November 2009. Retrieved 23 March 2010.
  3. "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.
  4. "IDM Pharma receives not approvable letter for Mifamurtide for treatment of osteosarcoma". The Medical News. 2007-08-28. Retrieved 2009-11-12.
  5. Template:Cite
  6. 6.0 6.1 EMA (2009-03-06). "Mepact: Product Information. Annex I: Summary of Product Characteristics" (PDF). p. 2. Retrieved 2009-11-12.
  7. EMA (2009-05-06). "Mepact: European Public Assessment Report. Summary for the public" (PDF). p. 1. Retrieved 2009-11-12.
  8. PMID 19671023 (PMID 19671023)
    Citation will be completed automatically in a few minutes. Jump the queue or expand by hand
  9. PMID 18235123 (PMID 18235123)
    Citation will be completed automatically in a few minutes. Jump the queue or expand by hand
  10. PMID 15774791 (PMID 15774791)
    Citation will be completed automatically in a few minutes. Jump the queue or expand by hand
  11. Template:Harv
  12. Template:Harv
  13. Template:Harv
  14. Template:Harv
  15. Fidler, I. J. (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.
  16. Prous, J. R.; Castaner, J. (1989). "ENV 2-3/MTP-PE". Drugs Fut. 14 (3): 220.
  17. Brundish, D. E.; 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.