Immunostimulants, Other immunostimulants. ATC Code:
Pharmacology: Pharmacodynamics: 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.
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 Adverse Reactions).
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 (see Figure 1). In a randomised phase III study of 678 patients (age range from 1.4 to 30.6 years) with newly-diagnosed resectable high-grade osteosarcoma, 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]). (See Figure 1.)
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Pharmacokinetics: General Introduction:
The pharmacokinetics of mifamurtide have been characterized in healthy adult subjects following a 4 mg intravenous infusion and in pediatric and adult patients with osteosarcoma following a 2 mg/m2
In 21 healthy adult subjects mifamurtide was cleared rapidly from serum (minutes) with a half-life of 2.05 ± 0.40 hours, resulting in a very low serum concentration of total (liposomal and free) mifamurtide. The mean AUC was 17.0±4.86 h x nM and Cmax was 15.7+/-3.72 nM.
In 28 osteosarcoma patients aged 6 to 39 years serum total (liposomal and free) mifamurtide concentrations declined rapidly with a mean half-life of 2.04±0.456 hours. BSA-normalized clearance and half-life were similar across the age range and consistent with that determined in healthy adult subjects, supporting the recommended dose of 2 mg/m2
In a 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 last infusion 11 or 12 weeks later, were almost superimposable and the mean AUC values of the free mifamurtide after the first and last infusion were similar. These data indicate that neither total nor free mifamurtide accumulated during the treatment period.
At 6 hours after injection of radiolabelled liposomes containing 1 mg mifamurtide, radioactivity was found in liver, spleen, nasopharynx, thyroid, and, to a lesser extent, in lung. The liposomes were phagocytosed by cells of the reticuloendothelial system. In 2 of 4 patients with lung metastases, radioactivity was associated with lung metastases.
Metabolism of liposomal-MTP-PE has not been studied in humans.
After intravenous administration in healthy adult subjects and in osteosarcoma patients, mifamurtide was rapidly cleared from serum with a half-life of 2.05±0.40 hours and 2.04±0.456 hours respectively.
After injection of radiolabelled liposomes containing mifamurtide, mean half-life of radiolabelled material was biphasic with an α phase of about 15 minutes and a terminal half-life of approximately 18 hours.
Renal Impairment: The Pharmacokinetics of a single 4 mg dose of mifamurtide following a 1 hour intravenous infusion were evaluated in adult volunteers with mild (n=9) or moderate (n=8) renal impairment and in age-, -sex- and weight-matched healthy adults with normal renal function (n=16), There was no effect of mild (50mL/min≤CLcr≤80mL/min) or moderate (30 mL/min≤CLcr≤50mL/min) renal insufficiency on the clearance of total MTP-PE when compared with that observed in healthy adult subjects with normal renal function (CLcr>80mL/min).
Hepatic Impairment: The pharmacokinetics of a single 4 mg dose of mifamurtide following a 1 hour intravenous infusion were evaluated in adult volunteers with mild (Child-Pugh class A: n=9) or moderate (Child-Pugh class B: n=8) hepatic impairment and in age-, sex-, and weight-matched healthy adults with normal hepatic function (n=19).There was no effect of mild hepatic impairment on the systemic exposure (AUCinf) of total MTP-PE. Moderate hepatic impairment resulted in a small increase in AUCinf of total MTP-PE, with the geometric least square mean ratio (expressed as %) for moderate hepatic impairment in reference to the matched normal hepatic function group being 119% (90% CI: 94.1%-151%).This effect is not considered to be clinically meaningful as the maximum tolerated dose (4-6 mg/m2
) of mifamurtide is 2-3 times the recommended dose (2mg/m2
Toxicology: Preclinical Safety Data:
In sensitive species (rabbit and dog) the highest daily dose of liposomal mifamurtide that did not cause adverse effects was 0.1 mg/kg, corresponding to 1.2 and 2 mg/m2
, respectively. The no-adverse-effect level for MEPACT in animals corresponds roughly to the 2 mg/m2
recommend dose for humans.
Data from a six month dog study of daily intravenous injections of up to 0.5 mg/kg (10 mg/m2
) MEPACT provide an 8- to 19-fold cumulative exposure safety margin for overt toxicity for the intended clinical dose in humans. Major toxic effects associated with these high daily and cumulative doses of MEPACT were mainly exaggerated pharmacological effects: pyrexia, signs of pronounced inflammatory response manifested as synovitis, bronchopneumonia, pericarditis and inflammatory necrosis of the liver and bone marrow. The following events were also observed: haemorrhage and prolongation of coagulation times, infarcts, morphological changes in the wall of small arteries, oedema and congestion of the central nervous system, minor cardiac effects, and slight hyponatraemia. MEPACT was not mutagenic and did not cause teratogenic effects in rats and rabbits. Embryotoxic effects were observed only at maternal toxic levels.
There were no results from general toxicity studies that suggested harmful effects on male or female reproductive organs. Specific studies addressing reproductive function, perinatal toxicity and carcinogenic potential have not been performed.