Mifamurtide

Identification

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Name
Mifamurtide
Accession Number
DB13615
Type
Small Molecule
Groups
Approved, Experimental
Description

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].

Structure
Thumb
Synonyms
  • Mifamurtida
  • Mifamurtide
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Mepact4 mgIntravenousTakeda France Sas2009-03-06Not applicableEu
Categories
UNII
1LM890Q4FY
CAS number
838853-48-8
Weight
Average: 1277.515
Monoisotopic: 1276.74102124
Chemical Formula
C59H110N6NaO20P
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

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].

Associated Conditions
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].

TargetActionsOrganism
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].

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].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AceclofenacThe therapeutic efficacy of Mifamurtide can be decreased when used in combination with Aceclofenac.
AcemetacinThe therapeutic efficacy of Mifamurtide can be decreased when used in combination with Acemetacin.
Acetylsalicylic acidThe therapeutic efficacy of Mifamurtide can be decreased when used in combination with Acetylsalicylic acid.
AlclofenacThe therapeutic efficacy of Mifamurtide can be decreased when used in combination with Alclofenac.
AldosteroneThe therapeutic efficacy of Mifamurtide can be decreased when used in combination with Aldosterone.
AlminoprofenThe therapeutic efficacy of Mifamurtide can be decreased when used in combination with Alminoprofen.
AminophenazoneThe therapeutic efficacy of Mifamurtide can be decreased when used in combination with Aminophenazone.
AntipyrineThe therapeutic efficacy of Mifamurtide can be decreased when used in combination with Antipyrine.
AntrafenineThe therapeutic efficacy of Mifamurtide can be decreased when used in combination with Antrafenine.
AzapropazoneThe therapeutic efficacy of Mifamurtide can be decreased when used in combination with Azapropazone.
Food Interactions
Not Available

References

General References
  1. 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. [PubMed:21226638]
  2. 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. [PubMed:20596505]
  3. 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. [PubMed:20481644]
  4. 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. [PubMed:24134216]
  5. EMA Summary of product characteristics: Mepact, INN-mifamurtide [Link]
External Links
ChemSpider
32700228
Wikipedia
Mifamurtide
ATC Codes
L03AX15 — Mifamurtide
MSDS
Download (77.9 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentSarcoma, Osteogenic1
2RecruitingTreatmentSarcoma, Osteogenic1
Not AvailableCompletedNot AvailableSarcoma, Osteogenic1
Not AvailableTerminatedNot AvailableSarcoma, Osteogenic1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00132 mg/mLALOGPS
logP5.5ALOGPS
logP5.57ChemAxon
logS-6ALOGPS
pKa (Strongest Acidic)1.9ChemAxon
pKa (Strongest Basic)-3.5ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count15ChemAxon
Hydrogen Donor Count9ChemAxon
Polar Surface Area386.77 Å2ChemAxon
Rotatable Bond Count58ChemAxon
Refractivity314.96 m3·mol-1ChemAxon
Polarizability139.44 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Targets

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
  1. 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. [PubMed:21226638]
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
  1. 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. [PubMed:21226638]
  2. 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. [PubMed:20596505]

Drug created on June 23, 2017 14:45 / Updated on December 16, 2018 07:01