Mifamurtide

Identification

Summary

Mifamurtide is a muramyl dipeptide derivative used to treat high grade, resectable, non-metastatic osteosarcoma after surgical resection.

Brand Names

Mepact

Generic Name

Mifamurtide

DrugBank Accession Number

DB13615

Background

Mifamurtide is an immunomodulator with antitumor activity via activation of macrophages and monocytes. Also called L-MTP-PE, mifamurtide may be a liposomal form of of the active ingredient MTP-PE, which is a synthetic, less pyrogenic, and longer-acting derivative of muramyl dipeptide (MDP). MDP is a motif present in all gram-positive and gram-negative bacterial walls that is recognized by different signalling molecules and activators such as nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) and toll-like receptors present in macrophages and monocytes. The overall result of MDP recognition leads to the production of proinflammatory cytokines and promotion of bactericidal and tumoricidal effects ². As a liposomal formulation, mifamurtide demonstrates an enhanced tumoricidal effect and improved safety profile ².

Mifamurtide is marketed in Europe as Mepact for intravenous infusion. It is administered as an adjuvant therapy to postoperative combination chemotherapy in pediatric, adolescent or adult patients with high-grade, resectable, non-metastatic osteosarcoma after macroscopically complete surgical resection. In the US, it is currently under investigation that holds orphan drug status for the treatment of osteosarcoma ³.

Osteosarcoma is the most common primary malignant bone tumor that usually arises in the metaphyses of long bone in children and adolescents ¹. The standard therapy for osteosarcoma is comprised of macroscopic surgical resection and multi-agent chemotherapy consisting of doxorubicin, cisplatin, high-dose methotrexate with leucovorin rescue, and ifosfamide ¹. While about 90% of patients with newly diagnosed osteosarcoma may achieve complete remission from first-line therapies, the prognosis is still poor for patients with non-metastatic osteosarcoma with lower 5-year event-free survival. In a large, randomized, open-label, multicenter, phase III trial, the treatment of mifamurtide in conjunction with three- or four-drug combination chemotherapy (doxorubicin, cisplatin, and high-dose methotrexate with, or without, ifosfamide) was associated with significant improvement in survival rates and good tolerance ³. The adverse events (AEs) associated with mifamurtide were generally mild to moderate in severity ⁴.

Type

Small Molecule

Groups

Approved, Experimental

Structure

Similar Structures

Weight: Average: 1277.515
Monoisotopic: 1276.74102124
Chemical Formula: C₅₉H₁₁₀N₆NaO₂₀P

Synonyms

Mifamurtida
Mifamurtide

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Pharmacology

Indication

Indicated in children, adolescents and young adults for the treatment of high-grade, resectable, non-metastatic osteosarcoma after macroscopically complete surgical resection, typically in combination with post-operative multi-agent chemotherapy ⁵.

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Associated Conditions

Indication Type	Indication	Approval Level	Age Group	Patient Characteristics
Adjunct therapy in treatment of	High-grade, nonmetastatic osteosarcoma	••••••••••••	•••••	••••••••••••••• •••••••• •••••••• •••••••••
Adjunct therapy in treatment of	High-grade, nonmetastatic osteosarcoma	••••••••••••	•••••••••	••••••••••••••• •••••••• •••••••• •••••••••
Adjunct therapy in treatment of	High-grade, nonmetastatic osteosarcoma	••••••••••••	••••••••••	••••••••••••••• •••••••• •••••••• •••••••••
Adjunct therapy in treatment of	Resectable, nonmetastatic osteosarcoma	••••••••••••	•••••	••••••••••••••• •••••••• •••••••• •••••••••
Adjunct therapy in treatment of	Resectable, nonmetastatic osteosarcoma	••••••••••••	•••••••••	••••••••••••••• •••••••• •••••••• •••••••••

Contraindications & Blackbox Warnings

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Pharmacodynamics

Mifamurtide stimulates the innate immunity by activating monocytes and macrophages. Within hours following administration of mifamurtide in healthy adults or patients with osteosarcoma NOS, elevated plasma levels of proinflammatory molecules, such as TNF-α, IL-6, and IL-1β, and other indicators of immune stimulation like C-reactive protein and neopterine were observed ². In vivo administration of mifamurtide in rat and mouse model resulted in inhibition of tumour growth of lung metastasis, skin and liver cancer, and fibrosarcoma ⁵. In addition, increased disease-free survival rate was demonstrated when mifamurtide was given as an adjuvant in dog models of osteosarcoma and hemangiosarcoma. Administration of mifamurtide was associated with transient neutropenia, usually when used in conjunction with chemotherapy. Pronounced inflammatory responses are uncommon ⁵.

Mechanism of action

It was discovered that tumor necrosis could be promoted by factors released by the host’s immune system (e.g. macrophages) in response to the endotoxins or bacterial products ². Mifamurtide is referred to as MTP-PE or L-MTP-PE (in case of the liposomal formulation), which is a fully synthetic derivative of muramyl dipeptide (MDP), which is a motif within the peptidoglycan polymer in the cell wall of bacteria.

MDP stimulates the immune system by being recognized by different pattern recognition molecules and receptors, such as nucleotide-binding oligomerization domain (NOD) 2 receptor and toll-like receptor (TLR). Similarly, mifamurtide acts as a ligand for TRL4 and NOD2. Involved in the innate immunity, NOD2 is an intracellular MDP sensor that is primarily expressed on monocytes, dendritic cells, and macrophages. It possesses an amino-terminal caspase recruitment domain, which is required to trigger nuclear factor-kappaB (NF-κB) signaling ². Activation of intracellular signaling transduction pathway NF-κB can promote inflammation and release of antimicrobial peptides, resulting in the production of pro-inflammatory cytokines like interleukin-1β (IL-1β), interleukin-6 (IL-6), and TNF-α, and other molecules such as chemokines and adhesion molecules ². Upon binding to TLR4, mifamurtide may activate extracellular-signal-regulated kinase 1/2 (ERK 1/2), nuclear factor-kappa B (NF-κB) and adaptor protein (AP)-1 ¹. Mifamurtide may also activate NLRP3, which is an essential component of the inflammasome, a protein complex that promotes the cleavage of procaspase 1 into its active form. Active caspase 1 further activates pro-inflammatory cytokines like IL-1β ². Furthermore, mifamurtide induces the expression of adhesion molecules including lymphocyte function-associated antigen (LFA)-1, intracellular adhesion molecule (ICAM)-1, and human leukocyte antigen (HLA)-DR ¹. Mifamurtide may interact with interferon (IFN)-γ to up-regulate tumoricidal activity ¹.

Upon intravenous administration, lipophilic mifamurtide is selectively phagocytosed by monocytes and macrophages followed by subsequent degradation of liposomal vesicles by the phagocytic cells. Then, MTP-PE is released into the cytosol where it interacts with Nod2 and activates the macrophages and monocytes ¹. Mifamurtide exerts a tumoricidal action via the same signalling pathway as MDP but with greater superiority because the lipophilic properties of MTP-PE cause higher cell uptake via passive transfer through the cytoplasmic membrane ¹. Incorporation of MTP-PE into liposomal structures allows better safety profile and more efficient distribution to the liver, spleen, and lungs after intravenous administration ¹.

Target	Actions	Organism
AToll-like receptor 4	ligand	Humans
ANucleotide-binding oligomerization domain-containing protein 2	ligand	Humans

Absorption

Due to rapid clearance from plasma, administration of mifamurtide is associated with a very low serum concentration of total (liposomal and free) drug. The mean AUC was 17.0 ± 4.86 h x nM and peak plasma concentration (Cmax) was 15.7 ± 3.72 nM following intravenous administration of 4 mg mifamurtide in healthy adult subjects ⁵. Variability in AUC and Cmax is reported to be low ⁴.

Volume of distribution

The mean volume of distribution at steady state (Vss) of total mifamurtide ranged from 225 to 28.7 healthy subjects after 4 mg intravenous infusion ⁴. There is no evidence of accumulation of L-MTP-PE or free MTP-PE (non-liposome-associated) ².

Protein binding

Not Available

Metabolism

Metabolism of liposomal MTP-PE has not been studied in humans ⁵. The liposomes are mainly phagocytosed by the cells of the reticuloendothelial system (RES) ².

Route of elimination

As there was no quantifiable urinary excretion of mifamurtide and renal impairment has no clinically significant impact on drug pharmacokinetics, renal clearance is not expected to contribute to the total systemic clearance of mifamurtide ⁴.

Half-life

Following intravenous administration of 4 mg mifamurtide in healthy adult subjects, the half life was 2.05 ± 0.40 hours. In pediatric and adult patients with psteosarcoma, the half life was 2.04 ± 0.456 hours after intravenous infusion of 2 mg/m^2 ⁵.

Clearance

The clearance from the plasma is rapid ⁵. Following 4 mg intravenous infusion, the mean clearance rate of total mifamurtide in healthy subjects ranged from 565 to 569 mL/min ⁴.

Adverse Effects

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Toxicity

There have been no reports of overdose with mifamurtide. Signs and symptoms that were associated with higher doses and/or were dose limiting were not life-threatening, and included fever, chills, fatigue, nausea, vomiting, headache and hypotension or hypertension ⁵. In cases of suspected overdose, appropriate supportive care is recommended. Gastrointestinal toxicity associated with nausea, vomiting and loss of apetite from mifamurtide therapy is commonly observed.

Mifamurtide was not mutagenic and did not cause teratogenic effects in rats and rabbits. Embryotoxic effects were observed only at maternal toxic levels. There is no evidence of mifamurtide generating harmful effects on male or female reproductive organs. Studies assessing reproductive function, perinatal toxicity and carcinogenicity have not been performed ⁵.

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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Aceclofenac	The therapeutic efficacy of Mifamurtide can be decreased when used in combination with Aceclofenac.
Acemetacin	The therapeutic efficacy of Mifamurtide can be decreased when used in combination with Acemetacin.
Acetylsalicylic acid	The therapeutic efficacy of Mifamurtide can be decreased when used in combination with Acetylsalicylic acid.
Alclofenac	The therapeutic efficacy of Mifamurtide can be decreased when used in combination with Alclofenac.
Aminophenazone	The therapeutic efficacy of Mifamurtide can be decreased when used in combination with Aminophenazone.

Food Interactions

No interactions found.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Mepact	Powder	4 mg	Intravenous	Takeda France Sas	2017-08-11	Not applicable

Chemical Identifiers

UNII: 1LM890Q4FY
CAS number: 83461-56-7
InChI Key: NGIYLSFJGRLEMI-MHTUOZSYSA-M
InChI: InChI=1S/C59H109N6O19P.Na.H2O/c1-7-9-11-13-15-17-19-21-23-25-27-29-31-33-52(71)80-41-47(84-53(72)34-32-30-28-26-24-22-20-18-16-14-12-10-8-2)42-82-85(78,79)81-38-37-61-57(75)43(3)62-51(70)36-35-48(56(60)74)65-58(76)44(4)63-59(77)45(5)83-55(54(73)50(69)40-67)49(39-66)64-46(6)68;;/h39,43-45,47-50,54-55,67,69,73H,7-38,40-42H2,1-6H3,(H2,60,74)(H,61,75)(H,62,70)(H,63,77)(H,64,68)(H,65,76)(H,78,79);;1H2/q;+1;/p-1/t43-,44-,45+,47+,48+,49-,50+,54+,55+;;/m0../s1
IUPAC Name: sodium (2R)-1-({2-[(2S)-2-[(4R)-4-carbamoyl-4-[(2S)-2-[(2R)-2-{[(2R,3R,4R,5R)-2-acetamido-4,5,6-trihydroxy-1-oxohexan-3-yl]oxy}propanamido]propanamido]butanamido]propanamido]ethyl phosphono}oxy)-3-(hexadecanoyloxy)propan-2-yl hexadecanoate hydrate
SMILES: O.[Na+].CCCCCCCCCCCCCCCC(=O)OC[C@H](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]([C@H](O)[C@H](O)CO)[C@@H](NC(C)=O)C=O)C(N)=O)OC(=O)CCCCCCCCCCCCCCC

References

General References

Ando K, Mori K, Corradini N, Redini F, Heymann D: Mifamurtide for the treatment of nonmetastatic osteosarcoma. Expert Opin Pharmacother. 2011 Feb;12(2):285-92. doi: 10.1517/14656566.2011.543129. [Article]
Kager L, Potschger U, Bielack S: Review of mifamurtide in the treatment of patients with osteosarcoma. Ther Clin Risk Manag. 2010 Jun 24;6:279-86. [Article]
Frampton JE: Mifamurtide: a review of its use in the treatment of osteosarcoma. Paediatr Drugs. 2010 Jun;12(3):141-53. doi: 10.2165/11204910-000000000-00000. [Article]
Venkatakrishnan K, Liu Y, Noe D, Mertz J, Bargfrede M, Marbury T, Farbakhsh K, Oliva C, Milton A: Pharmacokinetics and pharmacodynamics of liposomal mifamurtide in adult volunteers with mild or moderate hepatic impairment. Br J Clin Pharmacol. 2014 Jun;77(6):998-1010. doi: 10.1111/bcp.12261. [Article]
EMA Summary of product characteristics: Mepact, INN-mifamurtide [Link]

External Links

ChemSpider: 32700228
Wikipedia: Mifamurtide

MSDS

Download (77.9 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
2	Active Not Recruiting	Treatment	Osteosarcoma	2
2	Terminated	Treatment	Osteosarcoma	1
Not Available	Completed	Not Available	Osteosarcoma	1
Not Available	Terminated	Not Available	Osteosarcoma	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Powder	Intravenous; Parenteral	4 MG
Injection	Parenteral	4 mg
Powder	Intravenous	4 mg

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.00132 mg/mL	ALOGPS
logP	5.5	ALOGPS
logP	5.57	Chemaxon
logS	-6	ALOGPS
pKa (Strongest Acidic)	1.9	Chemaxon
pKa (Strongest Basic)	-3.5	Chemaxon
Physiological Charge	-1	Chemaxon
Hydrogen Acceptor Count	15	Chemaxon
Hydrogen Donor Count	9	Chemaxon
Polar Surface Area	386.77 Å²	Chemaxon
Rotatable Bond Count	58	Chemaxon
Refractivity	314.96 m³·mol^-1	Chemaxon
Polarizability	139.44 Å³	Chemaxon
Number of Rings	0	Chemaxon
Bioavailability	0	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å²)	Source type	Source
[M-H]-	330.2148	predicted	DeepCCS 1.0 (2019)
[M+H]+	331.868	predicted	DeepCCS 1.0 (2019)
[M+Na]+	338.02487	predicted	DeepCCS 1.0 (2019)

Targets

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Details1. Toll-like receptor 4

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Ligand

General Function: Transmembrane signaling receptor activity
Specific Function: Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and ...
Gene Name: TLR4
Uniprot ID: O00206
Uniprot Name: Toll-like receptor 4
Molecular Weight: 95679.19 Da

References

Ando K, Mori K, Corradini N, Redini F, Heymann D: Mifamurtide for the treatment of nonmetastatic osteosarcoma. Expert Opin Pharmacother. 2011 Feb;12(2):285-92. doi: 10.1517/14656566.2011.543129. [Article]

Details2. Nucleotide-binding oligomerization domain-containing protein 2

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Ligand

General Function: Involved in gastrointestinal immunity. Upon stimulation by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan, binds the proximal adapter receptor-interacting RIPK2, which recruits ubiquitin ligases as XIAP, BIRC2, BIRC3, INAVA and the LUBAC complex, triggering activation of MAP kinases and activation of NF-kappa-B signaling. This in turn leads to the transcriptional activation of hundreds of genes involved in immune response. Required for MDP-induced NLRP1-dependent CASP1 activation and IL1B release in macrophages (PubMed:18511561).
Specific Function: Actin binding
Gene Name: NOD2
Uniprot ID: Q9HC29
Uniprot Name: Nucleotide-binding oligomerization domain-containing protein 2
Molecular Weight: 115281.675 Da

References

Ando K, Mori K, Corradini N, Redini F, Heymann D: Mifamurtide for the treatment of nonmetastatic osteosarcoma. Expert Opin Pharmacother. 2011 Feb;12(2):285-92. doi: 10.1517/14656566.2011.543129. [Article]
Kager L, Potschger U, Bielack S: Review of mifamurtide in the treatment of patients with osteosarcoma. Ther Clin Risk Manag. 2010 Jun 24;6:279-86. [Article]

Drug created at June 23, 2017 20:45 / Updated at December 06, 2022 13:40

Mifamurtide

Identification

Structure for Mifamurtide (DB13615)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Collision Cross Sections (CCS)

Targets

References

References