MEPACT

Indications

• Treatment of high-grade, resectable, non-metastatic osteosarcoma after complete surgical resection

Dosage

Children: Refer to the BNF for Children for pediatric dosing guidelines.

Adults: The recommended dosage for adults is 4 mg administered as a powder for suspension for infusion, typically given once daily for 21 consecutive days in repeated 28-day cycles, up to 9 cycles, depending on tolerance.

Mechanism of action

Mifamurtide acts as a ligand for TLR4 and NOD2, which are pattern recognition receptors involved in innate immunity. By binding to these receptors, mifamurtide activates intracellular signaling pathways, including NF-κB and ERK 1/2, leading to the release of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. This immune activation promotes inflammation and facilitates tumor necrosis, enhancing the body's ability to combat malignancies.

Pharmacodynamics

Mifamurtide stimulates innate immune responses by activating monocytes and macrophages. Following administration, elevated levels of pro-inflammatory cytokines and immune markers are observed in plasma. Preclinical studies have shown that mifamurtide can inhibit tumor growth in various cancer models and improve disease-free survival in animal studies of osteosarcoma. Its use may be associated with transient neutropenia, particularly when combined with chemotherapy.

Pharmacokinetics

The pharmacokinetics of mifamurtide in humans has not been extensively characterized, but it is known to induce a rapid immune response post-administration. The drug is typically administered as a powder for suspension for infusion, and its absorption and distribution in the body are influenced by its interaction with immune cells. Clinical monitoring is recommended to assess for potential side effects and efficacy.

Contra-indications

• Active tuberculosis (confirmed)

Adverse effects

• Leucopenia
• Mucositis
• Nephrotoxicity
• Stomatitis
• Thrombocytopenia
• Erythema nodosum
• Eye disorders
• Influenza-like illness
• Interstitial lung disease
• Nephritis
• Renal abscess
• Renal failure
• Confusion
• Chills
• Cough
• Chest discomfort
• Dehydration
• Depression
• Dizziness
• Headache
• Hearing loss
• Hepatic pain
• Hyperhidrosis
• Hypertension
• Hypokalaemia
• Hypotension
• Hypothermia
• Increased risk of infection
• Insomnia
• Laryngeal pain
• Malaise
• Muscle complaints
• Nausea
• Oedema
• Pain
• Pallor
• Palpitations
• Neutropenia
• Nasal congestion
• Anxiety
• Anemia
• Appetite decreased
• Arthralgia
• Asthenia
• Cancer pain

Interactions

• Ciclosporin (severe - decreases efficacy)
• Corticosteroids (severe - decreases efficacy)
• NSAIDs (severe - decreases efficacy)
• Pimecrolimus (severe - decreases efficacy)
• Sirolimus (unknown - decreases efficacy)
• Tacrolimus (unknown - affects efficacy)

Precautions

• Screen for active tuberculosis prior to treatment
• Use caution in patients with a history of inflammatory disease

Pregnancy

Avoid use during pregnancy due to potential risks.

Breast-feeding

Avoid use during breastfeeding due to potential risks.

Storage

Store at room temperature, protect from light. Reconstituted solutions should be used immediately or as directed.

Formulations

• Mifamurtide 4 mg powder for suspension for infusion (Mepact)

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. 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.

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. _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.