er, chills, fatigue, nausea, vomiting, headache and hypo- or hypertension.
In the event of an overdose, it is recommended that appropriate supportive treatment be initiated. Supportive measures should be based on institutional guidelines and the clinical symptoms observed. Examples include paracetamol for fever, chills and headache and anti-emetics (other than steroids) for nausea and vomiting.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other cytokines and immunomodulators, ATC code: L03AX15
Mechanism of action
Mifamurtide (muramyl tripeptide phosphatidyl ethanolamine, MTP-PE) is a fully synthetic derivative of muramyl dipeptide (MDP), the smallest naturally-occurring immune stimulatory component of cell walls from Mycobacterium sp. It has similar immunostimulatory effects as natural MDP with the additional advantage of a longer half-life in plasma. MEPACT is a liposomal formulation specifically designed for in vivo targeting to macrophages by intravenous infusion.
MTP-PE is a specific ligand of NOD2, a receptor found primarily on monocytes, dendritic cells and macrophages. MTP-PE is a potent activator of monocytes and macrophages. Activation of human macrophages by MEPACT is associated with production of cytokines, including tumour necrosis factor (TNF-α), interleukin-1 (IL-1β), IL-6, IL-8, and IL-12 and adhesion molecules, including lymphocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1). In vitro-treated human monocytes killed allogeneic and autologous tumor cells (including melanoma, ovarian, colon, and renal carcinoma), but had no toxicity towards normal cells.
In vivo administration of MEPACT resulted in the inhibition of tumour growth in mouse and rat models of lung metastasis, skin and liver cancer, and fibrosarcoma. Significant enhancement of disease-free survival was also demonstrated in the treatment of dog osteosarcoma and hemangiosarcoma with MEPACT as adjuvant therapy. The exact mechanism by which MEPACT activation of monocytes and macrophages leads to antitumour activity in animals and humans is not yet known.
Clinical safety and efficacy
The safety of liposomal mifamurtide has been assessed in more than 700 patients with various kinds and stages of cancer and in 21 healthy adult subjects (see section 4.8).
MEPACT significantly increased the overall survival of patients with newly-diagnosed resectable high-grade osteosarcoma when used in conjunction with combination chemotherapy when compared to chemotherapy alone. In a randomised phase III study of 678 patients (age range from 1.4 to 30.6 years) with newly-diagnosed resectable high-grade osetosarcoma, the addition of adjuvant MEPACT to chemotherapy either doxorubicin cisplatin and methotrexate with or without ifosfamide resulted in a relative reduction in the risk of death of 28% (p = 0.0313, hazard ratio (HR) = 0.72 [95% confidence interval (CI): 0.53, 0.97]).
5.2 Pharmacokinetic properties
After intravenous administration in 21 healthy adult subjects mifamurtide was cleared rapidly from plasma (minutes), resulting in a very low plasma concentration of total (liposomal and free) mifamurtide. The mean AUC was 17.0 +/- 4.71 h x nM and Cmax was 15.7 +/- 3.72 nM. In separate study in 14 patients, mean serum concentration-time curves of total and free mifamurtide that were assessed after the first infusion of MEPACT and after a l |
