Emapalumab in Patients With Macrophage Activation Syndrome Associated With Still's Disease: A Population Pharmacokinetic/Pharmacodynamic Analysis

Abstract

Macrophage activation syndrome (MAS) is a life-threatening form of secondary haemophagocytic lymphohistiocytosis (HLH) associated with rheumatic diseases, most commonly Still's disease. This study aimed to develop a population pharmacokinetic (PK)/pharmacodynamic (PD) model for emapalumab, a fully human monoclonal antibody that targets interferon-gamma (IFNγ), in patients with MAS associated with Still's disease. A two-compartment disposition model based on data from patients with primary HLH administered emapalumab (1 mg/kg every 3 days, with possible increases to 3, 6 or 10 mg/kg) was re-estimated for patients with MAS administered emapalumab (6 mg/kg, then 3 mg/kg every 3 days until day 15 and twice weekly until day 28). An exploratory population PK/PD analysis comprising patients' PD data for total IFNγ, chemokine C-X-C motif ligand 9 (CXCL9) and ferritin was performed. Emapalumab clearance was generally linear and independent of total IFNγ levels in patients with MAS (n = 14). Estimated baseline levels of CXCL9 (a marker of IFNγ activity), soluble interleukin-2 receptor α (sIL-2Rα; a marker of hyperinflammation) and ferritin (a clinical marker of MAS disease activity) were 8400, 6550 and 15,300 μg/L, respectively. All three PD markers responded rapidly to changes in emapalumab concentration. Emapalumab almost completely suppressed CXCL9, sIL2-Rα, and ferritin production (estimated reduction in synthesis rate: 98.3%, 87%, and 99.6%, respectively). Population PK/PD modeling indicated that emapalumab rapidly suppresses markers of hyperinflammation in patients with MAS associated with Still's disease. Emapalumab dosing regimen used in clinical trials in patients with MAS is unlikely to need adjustment.