Mifamurtide

Mifamurtide (muramyl tripeptide phosphatidyl ethanolamine, MTP-PE) is a fully synthetic derivative of muramyl dipeptide (MDP), the smallest naturally occurring immune-stimulating component of the cell walls of Mycobacterium species. It has similar immunostimulatory effects to natural MDP. Mepact is a liposomal formulation designed to deliver it to macrophages after intravenous infusion.

Mechanism of Action

• NOD2 activation: MTP-PE is a specific ligand of NOD2, a receptor found mainly on monocytes, dendritic cells and macrophages, and is a potent activator of monocytes and macrophages. DrugBank also describes signalling through TLR4 and NF-κB.
• Targeting: after infusion the liposomes are taken up mainly by monocytes, macrophages and other cells of the reticuloendothelial system, which break them down and release MTP-PE inside the cell.
• Cytokines and adhesion molecules: activated human macrophages produce TNF-α, interleukin-1β, IL-6, IL-8 and IL-12, and adhesion molecules including LFA-1 and ICAM-1. Within hours of a dose, raised blood levels of inflammatory markers are seen.
• Anti-tumour activity: in vitro, treated human monocytes killed tumour cells (including melanoma, ovarian, colon and renal carcinoma cells) but not normal cells. In animals it inhibited tumour growth in lung metastasis, skin and liver cancer and fibrosarcoma models, and as adjuvant therapy it improved disease-free survival in dogs with osteosarcoma and haemangiosarcoma. The exact way in which macrophage activation leads to anti-tumour activity in animals and humans is not yet known.

Pharmacokinetics

• Exposure: mifamurtide is cleared from serum within minutes, so the serum concentration of total (liposomal and free) drug is very low. After a 4 mg infusion in 21 healthy adults, mean AUC was 17.0 ± 4.86 h·nM and Cmax was 15.7 ± 3.72 nM.
• Elimination: serum half-life was 2.05 ± 0.40 hours in healthy adults and 2.04 ± 0.456 hours in 28 patients aged 6 to 39 years given 2 mg/m². Clearance and half-life normalised to body surface area were similar across ages. Radiolabelled liposome material had a biphasic half-life, with an alpha phase of about 15 minutes and a terminal phase of about 18 hours.
• Distribution: 6 hours after radiolabelled liposomes containing 1 mg mifamurtide, radioactivity was found in the liver, spleen, nasopharynx, thyroid and, less, the lung. The liposomes were taken up by cells of the reticuloendothelial system.
• Metabolism: not studied in humans.
• Accumulation: none. Concentration curves after the first and last infusion, 11 or 12 weeks apart, were almost superimposable.
• Special populations: mild to moderate renal impairment (creatinine clearance 30 mL/min or more) and mild to moderate hepatic impairment (Child-Pugh A or B) have no clinically meaningful effect on pharmacokinetics, although variability is greater in moderate hepatic impairment. There are no pharmacokinetic data in severe renal or hepatic impairment.

• Osteosarcoma: treatment of high-grade resectable non-metastatic osteosarcoma in children, adolescents and young adults after macroscopically complete surgical resection, used in combination with post-operative multi-agent chemotherapy. Safety and efficacy were assessed in patients aged 2 to 30 years at initial diagnosis.

• Hypersensitivity to mifamurtide or to any of the excipients.
• Concurrent use of ciclosporin or other calcineurin inhibitors.
• Concurrent use of high-dose non-steroidal anti-inflammatory drugs (NSAIDs, cyclooxygenase inhibitors).

Mifamurtide was studied as a single agent in 248 patients, mostly with advanced cancer, in early phase I and II studies. The most frequent reactions are chills, pyrexia, fatigue, nausea, tachycardia and headache. Many of the very common reactions are thought to relate to its mechanism of action, and most events were mild or moderate.

Very common (≥1/10): anaemia, anorexia, headache, dizziness, tachycardia, hypertension, hypotension, dyspnoea, tachypnoea, cough, vomiting, diarrhoea, constipation, abdominal pain, nausea, hyperhidrosis, myalgia, arthralgia, back pain, pain in extremity, fever, chills, fatigue, hypothermia, pain, malaise, asthenia, chest pain.

Common (≥1/100 to <1/10): sepsis, cellulitis, nasopharyngitis, catheter site infection, upper respiratory tract infection, urinary tract infection, pharyngitis, herpes simplex infection; cancer pain; leukopenia, thrombocytopenia, granulocytopenia, febrile neutropenia; dehydration, hypokalaemia, decreased appetite; confusion, depression, insomnia, anxiety; paraesthesia, hypoaesthesia, tremor, somnolence, lethargy; blurred vision; vertigo, tinnitus, hearing loss; cyanosis, palpitations; phlebitis, flushing, pallor; pleural effusion, worsened dyspnoea, productive cough, haemoptysis, wheezing, epistaxis, exertional dyspnoea, sinus and nasal congestion, pharyngolaryngeal pain; upper and lower abdominal pain, dyspepsia, abdominal distension; liver pain; rash, pruritus, erythema, alopecia, dry skin; muscle spasms, neck, groin, bone, shoulder and chest wall pain, musculoskeletal stiffness; haematuria, dysuria, pollakiuria; dysmenorrhoea; peripheral oedema, oedema, mucosal inflammation, infusion-site erythema and reaction, catheter-site pain, chest discomfort, feeling cold; weight decreased; post-procedural pain.

Not known: pericardial effusion.

No reactions are listed as uncommon or rare. Serious reactions described in the SmPC include respiratory distress (in patients with asthma), neutropenic fever and sepsis, allergic reactions (rash, shortness of breath, grade 4 hypertension) and, uncommonly, pronounced inflammatory responses such as pericarditis and pleuritis.

• Ciclosporin and other calcineurin inhibitors: contraindicated, because of their hypothesised effect on splenic macrophages and mononuclear phagocytic function.
• High-dose NSAIDs (cyclooxygenase inhibitors): contraindicated, because in vitro they can block the macrophage-activating effect of liposomal mifamurtide.
• Corticosteroids: chronic or routine use should be avoided during treatment, since mifamurtide works by stimulating the immune system.
• Doxorubicin and other lipophilic medicines in the same chemotherapy regimen: the administration times should be separated.
• Chemotherapy: limited studies, although not conclusive, found no evidence that mifamurtide interferes with the anti-tumour effects of chemotherapy or the reverse. In a large randomised study, mifamurtide with medicines of known kidney toxicity (cisplatin, ifosfamide) or liver toxicity (high-dose methotrexate, ifosfamide) did not worsen those toxicities, and no dose adjustment was needed.
• Cytochrome P450: in vitro, liposomal and non-liposomal mifamurtide neither inhibit nor induce cytochrome P450 activity, so interactions with P450 substrates are not expected.

Treatment should be started and supervised by specialist physicians experienced in the diagnosis and treatment of osteosarcoma. Mepact is given by intravenous infusion over 1 hour and must not be given as a bolus injection. Reconstitution, filtration through the filter supplied in the carton and dilution before infusion are described in section 6.6 of the SmPC.

Recommended Dose

• 2 mg/m² of body surface area for all patients, as adjuvant therapy after surgical resection.
• Schedule: twice weekly, at least 3 days apart, for 12 weeks, then once weekly for a further 24 weeks. This makes 48 infusions in 36 weeks.
• It is used together with post-operative multi-agent chemotherapy.

Special Populations

• Adults over 30 years: there are not enough data to recommend use. No patient in the osteosarcoma studies was 65 or older, and the phase III study included only patients up to 30 years.
• Renal or hepatic impairment: no dose adjustment for mild to moderate renal impairment (creatinine clearance 30 mL/min or more) or mild to moderate hepatic impairment (Child-Pugh A or B). Caution is advised in moderate hepatic impairment, because pharmacokinetic variability is greater and safety data are limited, and in severe renal or hepatic impairment, where there are no pharmacokinetic data. Kidney and liver function should be monitored if mifamurtide continues beyond the end of chemotherapy, until all therapy is completed.
• Children under 2 years: safety and efficacy have not been established and no data are available.

Respiratory Distress

In patients with a history of asthma or other chronic obstructive pulmonary disease, preventive bronchodilators should be considered. Two patients with pre-existing asthma developed mild to moderate respiratory distress. If a severe respiratory reaction occurs, the infusion is stopped and appropriate treatment started.

Neutropenia

Transient neutropenia is commonly seen, usually with chemotherapy. Episodes of neutropenic fever should be monitored and managed. Mifamurtide may be given during neutropenia, but fever attributed to it should be watched closely. Fever or chills lasting more than 8 hours after a dose should be checked for possible sepsis.

Inflammatory Response

Signs of a pronounced inflammatory response, including pericarditis and pleuritis, were uncommon. Use caution in patients with autoimmune, inflammatory or other collagen disease, and watch for signs such as arthritis or synovitis that suggest an uncontrolled inflammatory reaction.

Cardiovascular Disorders

Patients with a history of venous thrombosis, vasculitis or unstable cardiovascular disorders should be monitored closely. If symptoms persist and worsen, treatment is delayed or stopped. Haemorrhage was seen in animals at very high doses and is not expected at the recommended dose, but clotting parameters should be checked after the first dose and again after several doses.

Allergic Reactions

Occasional allergic reactions have occurred, including rash, shortness of breath and grade 4 hypertension. They can be hard to tell from exaggerated inflammatory responses, so patients are monitored for signs of allergy.

Gastrointestinal Toxicity

Nausea, vomiting and loss of appetite are very common. The toxicity may be worse with high-dose multi-agent chemotherapy and was linked to more use of parenteral nutrition.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no data in pregnant women and animal studies are insufficient for reproductive toxicity. Mifamurtide is not recommended in pregnancy or in women of childbearing potential not using effective contraception.
• Breastfeeding: it is unknown whether mifamurtide passes into human milk, and this has not been studied in animals. Whether to continue or stop breastfeeding or therapy should weigh the benefit of breastfeeding to the child against the benefit of therapy to the woman.
• Fertility: no dedicated fertility studies have been done.

Sodium

Each dosage unit contains less than 1 mmol (23 mg) of sodium.

Effect on Driving

Mepact has a moderate influence on the ability to drive and use machines. Dizziness, vertigo, fatigue and blurred vision are very common or common effects.

Store the vials in a refrigerator at 2–8 °C and do not freeze them. Keep the vial in the outer carton to protect it from light. The cold chain should be kept unbroken from supplier to the hospital pharmacy. After reconstitution, the suspension is stable for 6 hours at up to 25 °C; use it immediately and do not refrigerate or freeze it. Each carton holds one 50 mL glass vial and one single-use sterile filter.

• Unopened vial: 3 years.
• Reconstituted suspension: chemical and physical stability has been shown for 6 hours up to 25 °C. From a microbiological point of view, immediate use is recommended; the reconstituted, filtered and diluted solution must not be kept longer than 6 hours at 25 °C, and must not be refrigerated or frozen.

Prescription only (Rx), on the prescription of specialist physicians experienced in the diagnosis and treatment of osteosarcoma. Mepact is given as a hospital infusion and must be kept at 2–8 °C, so it is supplied to the hospital or clinic that administers it, under cold-chain conditions.