Mifamurtida

Uses

Mifamurtida is a muramyl dipeptide derivative used to treat high grade, resectable, non-metastatic osteosarcoma after surgical resection.

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 .

Mifamurtida is also used to associated treatment for these conditions: High-grade, nonmetastatic Osteosarcoma, Resectable, nonmetastatic Osteosarcoma

How Mifamurtida works

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 . Mifamurtida 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 . Mifamurtida 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 . Mifamurtida 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 . Mifamurtida 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 .

Toxicity

There have been no reports of overdose with mifamurtide. Signs and symptoms that were associated with higher doses and/or were dose limiting were not life-threatening, and included fever, chills, fatigue, nausea, vomiting, headache and hypotension or hypertension . In cases of suspected overdose, appropriate supportive care is recommended. Gastrointestinal toxicity associated with nausea, vomiting and loss of apetite from mifamurtide therapy is commonly observed.

Mifamurtida was not mutagenic and did not cause teratogenic effects in rats and rabbits. Embryotoxic effects were observed only at maternal toxic levels. There is no evidence of mifamurtide generating harmful effects on male or female reproductive organs. Studies assessing reproductive function, perinatal toxicity and carcinogenicity have not been performed .

Food Interaction

Volume of Distribution

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) .

Elimination Route

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 .

Half Life

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 .

Clearance

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 .

Elimination Route

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 .

Innovators Monograph

You find simplified version here Mifamurtida