Emapalumab-lzsg is a monoclonal antibody that binds to and neutralizes interferon gamma (IFNγ). Nonclinical data suggest that IFNγ plays a pivotal role in the pathogenesis of HLH by being hypersecreted.
Emapalumab-lzsg reduces the plasma concentrations of CXCL9, a chemokine induced by IFNγ.
At a dose of 3 mg/kg emapalumab does not prolong the QT interval to any clinically relevant extent.
The pharmacokinetics of emapalumab-lzsg were evaluated in healthy adult subjects and in patients with primary HLH.
Following a 1 mg/kg emapalumab-lzsg dose, median steady state peak concentration was 44 mcg/mL, which was 2.9 times higher than after the first dose. The median steady state trough concentration was 25 mcg/mL, which was 4.3 times higher than after the first dose. Emapalumab-lzsg AUC increases slightly more than proportionally between 1 and 3 mg/kg doses, and less than proportionally at 3, 6, and 10 mg/kg doses.
Emapalumab-lzsg exhibits target-mediated clearance dependent on IFNγ production, which can vary between and within patients as a function of time and can affect the recommended dosage. Emapalumab-lzsg steady state is achieved by the 7th infusion when the IFNγ production is moderate. At high IFNγ production, steady-state is reached earlier due to a shorter half-life.
The central and peripheral volumes of distribution in a subject with body weight of 70 kg are 4.2 and 5.6 L, respectively.
Emapalumab-lzsg elimination half-life is approximately 22 days in healthy subjects, and ranged from 2.5 to 18.9 days in HLH patients.
Emapalumab-lzsg clearance is approximately 0.007 L/h in healthy subjects.
In patients, the total clearance of emapalumab-lzsg was significantly influenced by the production of IFNγ, demonstrating target mediated clearance of emapalumab-lzsg.
The metabolic pathway of emapalumab-lzsg has not been characterized. Like other protein therapeutics, emapalumab is expected to be degraded into small peptides and amino acids via catabolic pathways.
Body weight (2 to 82 kg) was a significant covariate of emapalumab-lzsg pharmacokinetics, supporting body weight-based dosing.
No clinically significant differences in the pharmacokinetics of emapalumab-lzsg were observed based on age (0.02 to 56 year), sex (53% Females), race (71.4% Caucasian, 12.2% Asian and 8.2% Black), renal impairment including dialysis, or hepatic impairment (mild, moderate, and severe).
No drug-drug interaction studies have been conducted with emapalumab.
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