Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

Mechanism of Action
Emapalumab 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.

Pharmacodynamics
IFNγ Inhibition
Emapalumab reduces the plasma concentrations of CXCL9, a chemokine induced by IFNγ.
Cardiac Electrophysiology
At a dose of 3 mg/kg GAMIFANT does not prolong the QT interval to any clinically relevant extent.

Pharmacokinetic Properties

Pharmacokinetics
The pharmacokinetics of emapalumab were evaluated in healthy adult subjects and in patients with primary HLH.
Following a 1 mg/kg emapalumab 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 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 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 [see Dosage and Administration; Monitoring to Assess Safety (3)]. Emapalumab 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.
Distribution
The central and peripheral volumes of distribution in a subject with body weight of 70 kg are 4.2 and 5.6 L, respectively.
Elimination
Emapalumab elimination half-life is approximately 22 days in healthy subjects, and ranged from 2.5 to 18.9 days in HLH patients.
Emapalumab clearance is approximately 0.007 L/h in healthy subjects.
In patients, the total clearance of emapalumab was significantly influenced by the production of IFNγ, demonstrating target mediated clearance of emapalumab.
Metabolism


The metabolic pathway of emapalumab has not been characterized. Like other protein therapeutics, GAMIFANT is expected to be degraded into small peptides and amino acids via catabolic pathways.
Specific Populations
Body weight (2 to 82 kg) was a significant covariate of emapalumab pharmacokinetics, supporting body weight-based dosing.
No clinically significant differences in the pharmacokinetics of emapalumab 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).
Drug Interaction Studies
No drug-drug interaction studies have been conducted with GAMIFANT.