Population Pharmacokinetic Analysis of Emapalumab, a Fully Human, Anti-Interferon Gamma Monoclonal Antibody, in Children with Primary Hemophagocytic Lymphohistiocytosis

Introduction: Primary hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome characterized by pathologic immune activation and hyperinflammation. It typically manifests during infancy and is invariably fatal if untreated. Interferon gamma (IFNy) is considered a key contributor to the hyperinflammation of HLH. Thus, neutralization of IFNy could help control the disease until haematopoietic stem cell transplantation, the only curative treatment. Emapalumab, a fully human, anti-IFNy monoclonal antibody, binds to and neutralizes IFNy. Emapalumab is the first and only approved (FDA) treatment for primary HLH. It is indicated for the treatment of adult and pediatric patients with HLH with refractory, recurrent, or progressive disease, or intolerance to conventional HLH therapy.

Objective: To develop a population pharmacokinetic (PK) model to describe the PK profile of emapalumab.

Methods: PK data were obtained from patients with primary HLH administered emapalumab intravenously during an open-label, single-group, phase 2/3 clinical trial (NCT01818492) and as part of a compassionate use program. A population PK analysis was performed using nonlinear mixed effects modeling (NONMEM^® version 7.3.0). Predictive performance of the model was assessed using a visual predictive check.

Results: The PK of emapalumab was adequately described by a two-compartment model. All model parameters were estimated with good precision. Central and peripheral volumes of distribution were 0.059 and 0.079 L/kg, respectively. Exploratory graphical analysis showed that (i) IFNy production varied significantly between and within patients as a function of time; (ii) the higher the IFNy production, the faster the elimination of emapalumab due to target-mediated drug disposition; and (iii) the higher the IFNy production, the higher the dose of emapalumab required to reach the neutralizing concentration of IFNy (evidenced by a higher target-mediated clearance of emapalumab). Of the parameters examined, only body weight and total IFNy (free and bound) levels were found to significantly influence the PK of emapalumab. The allometric exponents of body weight for the volume of distribution and clearance were 1 (fixed) and 0.886 (95% confidence interval 0.68, 1.09), respectively. These values support the bodyweight-based dosing of emapalumab (i.e. mg/kg). At values of total IFNy from 10³ to 10⁶ pg/mL, the total clearance (linear + target mediated) of emapalumab ranged from 0.0012 to 0.0140 L/h for a bodyweight of 5 kg, with corresponding terminal half-lives from 17.5 to 2.3 days. This wide variance in clearances and half-lives partly explains the emapalumab dose adaptations that are required for treating primary HLH patients.

Conclusion: The population PK model reliably predicted serum concentrations of emapalumab in patients with primary HLH. The central and peripheral volumes of distribution were low, clearance was slow, and the terminal half-life long. The expected dynamic of the biology of IFNy was confirmed and included in the population PK model. Simulations using this model supported the proposed dosing scheme of emapalumab in patients with primary HLH.