Narsoplimab inhibits MASP-2, the effector enzyme of the lectin pathway of the complement system, blocking lectin-dependent activation of complement component 3 (C3) and C4 without affecting the classical and alternative pathways of complement.
In hematopoietic stem cell transplant-associated thrombotic microangiopathy (TA-TMA), MASP-2 inhibition is thought to prevent lectin pathway-mediated cellular injury, including endothelial cell injury in small blood vessels.
The effect of narsoplimab on lectin pathway activity, assessed using inhibition of C4d deposition, was investigated in healthy subjects and patients with TA-TMA (TA-TMA Study). Narsoplimab concentration levels achieved in patients with TA-TMA resulted in >80% inhibition of lectin pathway activity. Based on pharmacokinetic/pharmacodynamic (PK/PD) modeling, a wash-out period of 6 weeks is sufficient to reduce narsoplimab concentrations to below pharmacologically active levels.
The PK profile of narsoplimab has been characterized in healthy subjects and in patients. PK of narsoplimab is less than dose-proportional for 2 and 4 mg/kg weekly IV dosing, with an accumulation ratio ranging from 1.02 to 1.75 at 4 mg/kg IV weekly dosing. Narsoplimab steady state (measured at day 36) geometric mean Cmax is 36.9 µg/mL, with geometric mean AUC0-tau of 2314 µg·h/mL following 4 mg/kg administered intravenously in healthy subjects. Narsoplimab steady state is reached after three once-weekly IV doses (day 15) of 4 mg/kg in healthy subjects.
After intravenous administration, peak plasma concentrations of narsoplimab occur approximately at the end of each infusion.
Narsoplimab is distributed in the blood and hydrophilic extravascular space with an average (CV%) volume of distribution of 10.9 L (65%) in patients.
Total clearance of narsoplimab is concentration-dependent, with an estimated mean (CV%) value of 0.12 L/hour (68%) in patients. The mean (CV%) terminal elimination half-life was estimated to be 209 hours (73%) in patients.
Narsoplimab is expected to be metabolized into small peptides and amino acids by catabolic pathways.
No biotransformation or excretion studies have been conducted.
Body weight was a significant covariate affecting the PK of narsoplimab. No clinically significant differences in PK of narsoplimab were observed based on race or sex.
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