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			{{Short description|Pharmaceutical drug}}
	{{Drugbox
			{{Infobox drug
	| IUPAC_name = 2--propanoyl}-<small>L</small>-alanyl-<small>D</small>-isoglutaminyl-<small>L</small>-alanyl)amino]ethyl (2''R'')-2,3-bis(hexadecanoyloxy)propyl hydrogen phosphate
			| Verifiedfields = changed
	| image = Mifamurtide.svg
			| Watchedfields = changed
	| width = 300
			| verifiedrevid = 407798436
	| CAS_number = 83461-56-7
			| IUPAC_name = 2--propanoyl}-<small>L</small>-alanyl-<small>D</small>-isoglutaminyl-<small>L</small>-alanyl)amino]ethyl (2''R'')-2,3-bis(hexadecanoyloxy)propyl hydrogen phosphate
	| CAS_supplemental = <br />{{CAS|838853-48-8}} (mifamurtide sodium · xH<sub>2</sub>O)
			| image = Mifamurtide.svg
	| ATC_prefix = L03
			| width = 300
	| ATC_suffix = AX15
	| ATC_supplemental =
			<!--Clinical data-->
	| PubChem = 23725093
			| tradename = Mepact
	| ChemSpiderID =
			| licence_EU = yes
	| DrugBank =
			| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
	| KEGG = D06619
			| pregnancy_US = <!-- A / B / C / D / X -->
	| chemical_formula =
			| pregnancy_category = not investigated
	| C=59 | H=109 | N=6 | O=19 | P=1
			| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
	| molecular_weight = 1237.499 g/mol
			| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->
	| smiles = CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCCNC(=O)(C)NC(=O)CC(NC(=O)(C)NC(=O)(C)O1C(O)(CO)O(O)1NC(C)=O)C(N)=O)OC(=O)CCCCCCCCCCCCCCC
			| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C -->
	| bioavailability = N/A
			| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
	| protein_bound =
	| metabolism =		| legal_status = Rx
	| elimination_half-life = minutes (in plasma)<br />18 hrs (terminal)
	| excretion =
	| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
	| pregnancy_US = <!-- A / B / C / D / X -->
	| pregnancy_category= not investigated
	| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
	| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->
	| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C -->
	| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
	| legal_status = Rx
	| routes_of_administration = ] ] infusion over one hour		| routes_of_administration = ] ] infusion over one hour
	| licence_EU = Mepact
	}}
			<!--Pharmacokinetic data-->
	'''Mifamurtide''' (trade name '''Mepact''', marketed by ]) is a drug against ], a kind of bone ] mainly affecting children and young adults, which is lethal in about a third of cases. The drug was approved in Europe in March 2009.
			| bioavailability = N/A
			| protein_bound =
			| metabolism =
			| elimination_half-life = minutes (in plasma)<br />18 hrs (terminal)
			| excretion =
			<!--Identifiers-->
	== History ==
			| CAS_number_Ref = {{cascite|correct|??}}
	The drug was invented by ] (now ]) in the early 1980s and sold to ] in the 1990s. In 2003, ] bought the rights and developed it further.<ref name="DrugsRD">{{pmid|18298131}}</ref> IDM Pharma was acquired by Takeda along with mifamurtide in June 2009.<ref>{{cite news|title=First Treatment to Improve Survival in 20 Years Now Available for Patients With Osteosarcoma (Bone Cancer)|publisher=Takeda|date=November 2009|accessdate=23 March 2010|url=http://www.presseportal.de/pm/77160/1554185/takeda_pharmaceutical_company_limited}}</ref>
			| CAS_number = 83461-56-7
			| CAS_supplemental = <br />{{CAS|838853-48-8}} (mifamurtide sodium{{Hydrate|{{mvar|x}}}})
			| ATC_prefix = L03
			| ATC_suffix = AX15
			| ATC_supplemental =
			| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
			| DrugBank =
			| PubChem = 11672602
			| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
			| ChemSpiderID = 9847332
			| UNII_Ref = {{fdacite|changed|FDA}}
			| UNII = EQD2NNX741
			| KEGG_Ref = {{keggcite|correct|kegg}}
			| KEGG = D06619
			<!--Chemical data-->
	Mifamurtide had already been granted ] status by the ] (FDA) in 2001, and the ] (EMEA) followed in 2004. It was approved in the 27 ] member states plus Iceland, Liechtenstein and Norway via a centralized marketing authorization in March 2009. The drug was denied approval by the FDA in 2007.<ref>{{cite news|url=http://www.prnewswire.co.uk/cgi/news/release?id=251191|title=IDM Pharma's MEPACT (Mifamurtide, L-MTP-PE) Receives Approval in Europe for Treatment of Patients with Non-Metastatic, Resectable Osteosarcoma|date=2009-03-09|publisher=PR Newswire|accessdate=2009-11-12}}</ref><ref>{{cite news|url=http://www.news-medical.net/news/2007/08/28/29154.aspx|title=IDM Pharma receives not approvable letter for Mifamurtide for treatment of osteosarcoma|date=2007-08-28|publisher=The Medical News|accessdate=2009-11-12}}</ref>
			| chemical_formula =
			| C=59 | H=109 | N=6 | O=19 | P=1
			| smiles = CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCCNC(=O)(C)NC(=O)CC(NC(=O)(C)NC(=O)(C)O1C(O)(CO)O(O)1NC(C)=O)C(N)=O)OC(=O)CCCCCCCCCCCCCCC
			| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
			| StdInChI = 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
			| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
			| StdInChIKey = JMUHBNWAORSSBD-WKYWBUFDSA-N
			}}
	== Indications ==
	Mifamurtide is indicated for the treatment of high-grade, non-], ] osteosarcoma following complete surgical removal in children, adolescents and young adults, aged two to 30 years.<ref name="DrugsRD" /><ref name="SPC">{{cite web|url=http://www.ema.europa.eu/humandocs/PDFs/EPAR/mepact/emea-combined-h802en.pdf|title=Mepact: Product Information. Annex I: Summary of Product Characteristics|author=EMEA|date=2009-03-06|page=2|format=PDF|accessdate=2009-11-12|ref=harv}}</ref><ref>{{cite web|url=http://www.emea.europa.eu/humandocs/PDFs/EPAR/mepact/H-802-en1.pdf|title=Mepact: European Public Assessment Report. Summary for the public|author=EMEA|date=2009-05-06|page=1|format=PDF|accessdate=2009-11-12}}</ref> Osteosarcoma is a type of bone cancer diagnosed in about 1,000 individuals in Europe and the USA per year, most under the age of 30.<ref>{{pmid|19671023}}</ref> The drug is used in combination with post-operative, multi-agent ] to kill remaining cancer cells and so help improve a patient's chance of overall survival.<ref name="SPC" />
			'''Mifamurtide''' (trade name '''Mepact''', marketed by ]) is a drug against ], a kind of bone ] mainly affecting children and young adults, which is lethal in over half of cases. The drug was approved in Europe in March 2009.
	In a phase III ] in about 800 newly diagnosed osteosarcoma patients, mifamurtide was combined with the chemotherapeutic agents ] and ], with or without ] and ]. The ] could be lowered by 30% versus chemotherapy plus ]. Six years after the treatment, 78% of patients were still alive. This equals an absolute risk reduction of 8% (]=0.03).<ref name="DrugsRD" />
	== Adverse effects ==		== Medical uses ==
			Mifamurtide is indicated for the treatment of high-grade, non], ] osteosarcoma following complete surgical removal in children, adolescents, and young adults, aged two to 30 years.<ref name="DrugsRD" /><ref name="SPC">{{cite web|ref={{sfnref|EMA|2009-03-06}}|title=Mepact: Product Information. Annex I: Summary of Product Characteristics |author=EMA |date=2009-03-06|page=2|access-date=2009-11-12 |url=http://www.ema.europa.eu/humandocs/PDFs/EPAR/mepact/emea-combined-h802en.pdf}}{{dead link|date=October 2021}}</ref><ref>{{cite web |title=Mepact: European Public Assessment Report. Summary for the public|author=EMA |url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000802/WC500026562.pdf|date=2009-05-06|page=1|access-date=2016-10-06}}</ref> Osteosarcoma is diagnosed in about 1,000 individuals in Europe and the USA per year, most under the age of 30.<ref>{{cite journal | vauthors = Meyers PA | title = Muramyl tripeptide (mifamurtide) for the treatment of osteosarcoma | journal = Expert Review of Anticancer Therapy | volume = 9 | issue = 8 | pages = 1035–49 | date = August 2009 | pmid = 19671023 | doi = 10.1586/era.09.69 | s2cid = 29512704 }}</ref> The drug is used in combination with postoperative, multiagent ] to kill remaining cancer cells and improve a patient's chance of overall survival.<ref name="SPC" />
	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.<ref name="PMID18235123">{{pmid|18235123}}</ref><ref name="PMID15774791">{{pmid|15774791}}</ref> Common side effects include ] (ca. 90%), vomiting, ] and ] (ca. 50%), ]s, ], ], headache, ] and ] (>10%).<ref name="DrugsRD" /><ref>{{harv|EMEA|2009|pp=5–7}}</ref>
			In a phase-III ] in about 800 newly diagnosed osteosarcoma patients, mifamurtide was combined with the chemotherapeutic agents ] and ], with or without ] and ]. The ] could be lowered by 30% versus chemotherapy plus ]. Six years after the treatment, 78% of patients were still alive. This equals an absolute risk reduction of 8% <!-- (]=0.03) -->.<ref name="DrugsRD" />
	== Pharmacokinetics ==
	After application of the ] infusion, the drug is cleared from the plasma within minutes and is concentrated in lung, liver, ], ], and ]. The terminal half-life is 18 hours. In patients receiving a second treatment after 11–12 weeks, no accumulation effects were observed.<ref>{{harv|EMEA|2009|p=8}}</ref>
	== Pharmacodynamics ==		== 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.<ref name="pmid18235123">{{cite journal | vauthors = Meyers PA, Schwartz CL, Krailo MD, Healey JH, Bernstein ML, Betcher D, Ferguson WS, Gebhardt MC, Goorin AM, Harris M, Kleinerman E, Link MP, Nadel H, Nieder M, Siegal GP, Weiner MA, Wells RJ, Womer RB, Grier HE | display-authors = 6 | title = Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival--a report from the Children's Oncology Group | journal = Journal of Clinical Oncology | volume = 26 | issue = 4 | pages = 633–8 | date = February 2008 | pmid = 18235123 | doi = 10.1200/JCO.2008.14.0095 | doi-access = free }}</ref><ref name="pmid15774791">{{cite journal | vauthors = Meyers PA, Schwartz CL, Krailo M, Kleinerman ES, Betcher D, Bernstein ML, Conrad E, Ferguson W, Gebhardt M, Goorin AM, Harris MB, Healey J, Huvos A, Link M, Montebello J, Nadel H, Nieder M, Sato J, Siegal G, Weiner M, Wells R, Wold L, Womer R, Grier H | display-authors = 6 | title = Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate | journal = Journal of Clinical Oncology | volume = 23 | issue = 9 | pages = 2004–11 | date = March 2005 | pmid = 15774791 | doi = 10.1200/JCO.2005.06.031 | doi-access = free }}</ref> Common side effects include ] (about 90%), vomiting, ] and ] (about 50%), ]s, ], ], headache, ] and ] (>10%).<ref name="DrugsRD" /><ref>{{harv|EMA|2009-03-06|pp=5–7}}</ref>
	Mifamurtide is a fully synthetic derivative of ] (MDP), the smallest naturally-occurring immune stimulatory component of cell walls from '']'' species. It has similar immunostimulatory effects as natural MDP with the advantage of a longer half-life in plasma.
	] is a ] which is found in several kinds of ]s, mainly ] and ]. It recognises muramyl dipeptide, a component of the cell wall of ]. Mifamurtide simulates a bacterial infection by binding to NOD2, activating white cells. This results in an increased production of ], ], ], ], ] and other ]s, as well as ]. The activated white cells attack cancer cells, but not, at least '']'', other cells.<ref>{{harv|EMEA|2009|pp=7–8}}</ref>
	== Interactions ==		== Interactions ==
	* Theoretical considerations suggest that ]s like ] and ] might interact with mifamurtide because of their effect on macrophages.		* Theoretical considerations suggest ]s like ] and ] might interact with mifamurtide because of their effect on macrophages.
	* High-dose ]s block the mechanism of mifamurtide ''in vitro''.		* High-dose ]s block the mechanism of mifamurtide ''in vitro''.
	Consequently, the combination of mifamurtide with these types of drugs is contraindicated. However, mifamurtide can be co-administered with low doses of NSAIDs. There is no evidence to suggest that mifamurtide interacts with the studied chemotherapeutics, or with the ] system.<ref>{{harv|EMEA|2009|p=4}}</ref>		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 ] system.<ref>{{harv|EMA|2009-03-06|p=4}}</ref>
			== Pharmacology ==
			=== Mechanism of action ===
			Mifamurtide is a fully synthetic derivative of ] (MDP), the smallest naturally occurring immune stimulatory component of cell walls from '']'' species. It has similar immunostimulatory effects as natural MDP with the advantage of a longer half-life in plasma.
			] is a ] which is found in several kinds of ]s, mainly ] and ]. It recognises muramyl dipeptide, a component of the cell wall of ]. Mifamurtide simulates a bacterial infection by binding to NOD2, activating white cells. This results in an increased production of ], ], ], ], ], and other ]s, as well as ]. The activated white cells attack cancer cells, but not, at least '']'', other cells.<ref>{{harv|EMA|2009-03-06|pp=7–8}}</ref>
			=== Pharmacokinetics ===
			After application of the ] infusion, the drug is cleared from the plasma within minutes and is concentrated in lung, liver, ], ], and ]. The terminal half-life is 18 hours. In patients receiving a second treatment after 11–12 weeks, no accumulation effects were observed.<ref>{{harv|EMA|2009-03-06|p=8}}</ref>
	== Chemistry ==		== Chemistry ==
	]		]
	Mifamurtide is muramyl ] ] (MTP-PE), a synthetic analogue of muramyl dipeptide. The side chains of the molecule give it a longer ] than the natural substance. Being a ], it accumulates in the ] of the liposomes in the infusion.<ref>{{cite journal|last=Fidler|first=I. J.|title=Efficacy of liposomes containing a lipophilic muramyl dipeptide derivative for activating the tumoricidal properties of alveolar macrophages in vivo|journal=Journal of Immunotherapy|volume=1|issue=1|year=1982|pages=43–55}}</ref>		Mifamurtide is muramyl tripeptide phosphatidylethanolamine (MTP-PE), a synthetic analogue of muramyl dipeptide. The side chains of the molecule give it a longer ] than the natural substance. The substance is applied encapsulated into ]s (L-MTP-PE). Being a ], it accumulates in the ] of the liposomes in the infusion.<ref>{{cite journal| vauthors = Fidler IJ, Sone S, Fogler WE, Smith D, Braun DG, Tarcsay L, Gisler RH, Schroit AJ |title=Efficacy of liposomes containing a lipophilic muramyl dipeptide derivative for activating the tumoricidal properties of alveolar macrophages in vivo|journal=Journal of Immunotherapy|volume=1|issue=1|year=1982|pages=43–55}}</ref>
	=== Synthesis ===		=== Synthesis ===
	One method of synthesis (shown left) is based on ] (DCC) assisted ] of ''N''-acetylmuramyl-<small>L</small>-alanyl-<small>D</small>-]-<small>L</small>-alanine with ], followed by a condensation with 2-aminoethyl-2,3-di]<nowiki>glycerylphosphoric</nowiki> acid in ] (Et<sub>3</sub>N).<ref>{{cite journal|last1=Prous|first1=J. R.|last2=Castaner|first2=J.|title=ENV 2-3/MTP-PE|journal=Drugs Fut.|volume=14|issue=3|year=1989|page=220}}</ref> A different approach (shown right) uses ''N''-acetylmuramyl-<small>L</small>-alanyl-<small>D</small>-isoglutamine, hydroxysuccinimide and alanyl-2-aminoethyl-2,3-dipalmitoylglycerylphosphoric acid;<ref>{{cite journal|last1=Brundish|first1=D. E.|last2=Wade|first2=R.|title=Synthesis of N-acetyl-D-muramyl-L-alanyl-D-iso-glutaminyl-L-alanyl-2-(1',2'-dipalmitoyl-sn-glycero-3'-phosphoryl)ethylamide of high specific radioactivity|journal=J Label Compd Radiopharm|volume=22|issue=1|year=1985|pages=29–35|doi=10.1002/jlcr.2580220105}}</ref> that is, the alanine is introduced in the second step instead of the first.		One synthesis method (shown first) is based on ] (DCC) assisted ] of {{not a typo|''N''-acetylmuramyl-<small>L</small>-alanyl-<small>D</small>-]-<small>L</small>-alanine}} with ], followed by a condensation with 2-aminoethyl-2,3-di]<nowiki>glycerylphosphoric</nowiki> acid in ] (Et<sub>3</sub>N).<ref>{{cite journal| vauthors = Prous J, Castaner J |title=ENV 2-3/MTP-PE|journal= Drugs of the Future|volume=14|issue=3|year=1989|page=220|doi=10.1358/dof.1989.014.03.85085}}</ref> A different approach (shown second) uses {{not a typo|''N''-acetylmuramyl-<small>L</small>-alanyl-<small>D</small>-isoglutamine}}, hydroxysuccinimide and {{not a typo|alanyl-2-aminoethyl-2,3-dipalmitoylglycerylphosphoric acid}};<ref>{{cite journal| vauthors = Brundish DE, Wade R |title=Synthesis of N-acetyl-D-muramyl-L-alanyl-D-iso-glutaminyl-L-alanyl-2-(1',2'-dipalmitoyl-sn-glycero-3'-phosphoryl)ethylamide of high specific radioactivity|journal=J Label Compd Radiopharm|volume=22|issue=1|year=1985|pages=29–35|doi=10.1002/jlcr.2580220105}}</ref> that is, the alanine is introduced in the second step instead of the first.
	{|class="wikitable" border="1"		{|class="wikitable" border="1"
	|-		|-
	|]		|]
	|]		|]
	|}		|}
			== History ==
			The drug was invented by ] (now ]) in the early 1980s and sold to ] in the 1990s. In 2003, ] bought the rights and developed it further.<ref name="DrugsRD">{{cite journal | title = Mifamurtide: CGP 19835, CGP 19835A, L-MTP-PE, liposomal MTP-PE, MLV 19835A, MTP-PE, muramyltripeptide phosphatidylethanolamine | journal = Drugs in R&D | volume = 9 | issue = 2 | pages = 131–5 | year = 2008 | pmid = 18298131 | doi = 10.2165/00126839-200809020-00007 }}</ref> IDM Pharma was acquired by Takeda along with mifamurtide in June 2009.<ref>{{cite news|title=First Treatment to Improve Survival in 20 Years Now Available for Patients With Osteosarcoma (Bone Cancer)|publisher=Takeda|date=November 2009|access-date=23 March 2010|url=http://www.presseportal.de/pm/77160/1554185/takeda_pharmaceutical_company_limited}}</ref>
			Mifamurtide had already been granted ] status by the ] (FDA) in 2001, and the ] (EMA) followed in 2004. It was approved in the 27 ] 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.<ref>{{Cite press release|url=http://www.prnewswire.co.uk/cgi/news/release?id=251191|title=IDM Pharma's MEPACT (Mifamurtide, L-MTP-PE) Receives Approval in Europe for Treatment of Patients with Non-Metastatic, Resectable Osteosarcoma|date=2009-03-09|publisher=PR Newswire|access-date=2009-11-12}}</ref><ref>{{cite news|url=http://www.news-medical.net/news/2007/08/28/29154.aspx|title=IDM Pharma receives not approvable letter for Mifamurtide for treatment of osteosarcoma|date=2007-08-28|publisher=The Medical News|access-date=2009-11-12}}</ref> Mifamurtide has been licensed by the EMA since March, 2009.<ref>{{citation |url=http://www.mepact.net/|title=Mepact for Healthcare Professionals |access-date=2009-11-12}}</ref>
	== References ==		== References ==
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	]		]
	]		]
			]
	]
	]
	]