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General Description:

Mifamurtide, identified by CAS number 83461-56-7, is a notable compound with significant therapeutic applications. 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 . As a liposomal formulation, mifamurtide demonstrates an enhanced tumoricidal effect and improved safety profile . 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 . Osteosarcoma is the most common primary malignant bone tumor that usually arises in the metaphyses of long bone in children and adolescents . 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 . 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 . The adverse events (AEs) associated with mifamurtide were generally mild to moderate in severity .

Indications:

This drug is primarily indicated for: 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 . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Mifamurtide undergoes metabolic processing primarily in: Metabolism of liposomal MTP-PE has not been studied in humans . The liposomes are mainly phagocytosed by the cells of the reticuloendothelial system (RES) . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Mifamurtide are crucial for its therapeutic efficacy: 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 . Variability in AUC and Cmax is reported to be low . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Mifamurtide is an important consideration for its dosing schedule: 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 . This determines the duration of action and helps in formulating effective dosing regimens.

Route of Elimination:

The elimination of Mifamurtide from the body primarily occurs through: 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 . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Mifamurtide is distributed throughout the body with a volume of distribution of: 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 . There is no evidence of accumulation of L-MTP-PE or free MTP-PE (non-liposome-associated) . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Mifamurtide is a critical factor in determining its safe and effective dosage: The clearance from the plasma is rapid . Following 4 mg intravenous infusion, the mean clearance rate of total mifamurtide in healthy subjects ranged from 565 to 569 mL/min . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Mifamurtide exerts its therapeutic effects through: 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 . _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 . 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 . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Mifamurtide functions by: 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 . 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 . 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 . 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 . 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 . 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 . Mifamurtide may interact with interferon (IFN)-γ to up-regulate tumoricidal activity . 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 . 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 . Incorporation of MTP-PE into liposomal structures allows better safety profile and more efficient distribution to the liver, spleen, and lungs after intravenous administration . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Mifamurtide is categorized under the following therapeutic classes: Adjuvants, Immunologic, Amino Acids, Peptides, and Proteins, Amino Sugars, Antineoplastic and Immunomodulating Agents, Cancer immunotherapy, Carbohydrates, Glycerophosphates, Glycerophospholipids, Glycopeptides, Immunologic Factors, Immunotherapy, Lipids, Membrane Lipids, Muramic Acids, Peptides, Phosphatidic Acids, Phospholipids, Sugar Acids. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.