a 1 mg/kg emapalumab-lzsg dose, median steady state peak concentration was 44mcg/mL, which was 2.9 times higher than after the first dose. The median steady state troughconcentration 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/kgdoses, and less than proportionally at 3, 6, and 10 mg/kg doses.
Emapalumab-lzsg exhibits target-mediated clearance dependent on IFNγ production, which canvary between and within patients as a function of time and can affect the recommended dosage[see Dosage and Administration (2.2)]. Emapalumab-lzsg steady state is achieved by the 7thinfusion when the IFNγ production is moderate. At high IFNγ production, steady-state is reachedearlier 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-lzsg elimination half-life is approximately 22 days in healthy subjects, and rangedfrom 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 theproduction of IFNγ, demonstrating target mediated clearance of emapalumab-lzsg.
Metabolism
The metabolic pathway of emapalumab-lzsg has not been characterized. Like other proteintherapeutics, GAMIFANT is expected to be degraded into small peptides and amino acids viacatabolic pathways.
Specific Populations
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 observedbased on age (0.02 to 56 year), sex (53% Females), race (71.4% Caucasian, 12.2% Asian and8.2% Black), renal impairment including dialysis, or hepatic impairment (mild, moderate, andsevere).
Drug Interaction Studies
No drug-drug interaction studies have been conducted with GAMIFANT.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenicity or genotoxicity studies have been conducted with emapalumab-lzsg.
No studies have been conducted to eva luate the effects of emapalumab-lzsg on fertility; however,no adverse effects on male or female reproductive organs were observed in the 8- or 13-weekrepeat-dose toxicity studies in cynomolgus monkeys.
14 CLINICAL STUDIES
The efficacy of GAMIFANT was eva luated in a multicenter, open-label, single-arm trial NI-0501-04 (NCT01818492) in 27 pediatric patients with suspected or confirmed primary HLH witheither refractory, recurrent, or progressive disease during conventional HLH therapy or who wereintolerant of conventional HLH therapy.
Patients were required to fulfill the following criteria for enrollment: primary HLH based on amolecular diagnosis or family history consistent with primary HLH or five out of the 8 criteriafulfilled: fever, splenomegaly, cytopenias affecting 2 of 3 lineages in the peripheral blood(hemoglobin < 9 , platelets < 100 x 109/L, neutrophils < 1 x 109/L), hypertriglyceridemia (fastingtriglycerides > 3 mmol/L or ≥ 265 mg/dL) and/or hypofibrinogenemia (≤ 1.5 g/L),hemophagocytosis in bone marrow, spleen, or lymph nodes with no evidence of malignancy, lo |
