Bibi Hellinghus1, Jesper Falkesgaard Højen1, Magnus Fugger1, Christian Hollensen
1Novo Nordisk A/S
Objective: Ziltivekimab is a human monoclonal antibody that targets interleukin 6 (IL-6), a pro-inflammatory cytokine involved in various inflammatory processes. By binding to IL-6, ziltivekimab inhibits ligand-receptor interactions, and thus downstream signaling pathways. Therefore, quantifying the concentration of free IL-6 is of significant scientific and clinical interest. However, it is challenging to measure free IL-6 due to the very low concentrations, typically in the order of pg/mL. The concentration of free IL-6 is crucial for understanding changes in free IL-6 levels in response to ziltivekimab treatment as well as in communication with regulatory authorities and physicians. To address this issue, PK/PD modelling was used to quantify the concentration of free IL-6. This model was based on available PK and total IL-6 (bound and unbound) data from samples collected at baseline and during consecutive measurements, in accordance with clinical trial protocols. Method: PK and total IL-6 data were collected during clinical phase 1 and 2 trials, involving a total of 275 subjects with moderate to severe chronic kidney disease. The subjects were administered ziltivekimab at varying doses: 2, 6, or 20 mg intravenously or 7.5, 15, or 30 mg subcutaneously. The PK/PD analysis was performed using a non-linear mixed effect modelling approach in NONMEM. Both the PK and PK/PD part covariates were evaluated using a forward selection method with a p-value threshold of 0.05, followed by a backward inclusion method with a p-value threshold of 0.001. The PK/PD analysis was evaluated using the -2 log-likelihood objective function value, goodness-of-fit plots, and visual prediction checks. Data management, visualization of data, and model predictions were performed using R and Rstudio. Result: The PK/PD model was fitted sequentially, first to the PK of ziltivekimab and subsequently to the total IL-6 data. Initially, a two-compartment model with first order absorption and elimination was applied to the PK data of ziltivekimab. Using the post hoc estimates of the PK model, the total IL-6 was described by an indirect response model, which incorporated a baseline concentration of IL-6, a degradation rate constant (kdeg) of IL-6, and a dissociation constant (kd) for the binding of ziltivekimab to IL-6. Measured estimated glomerular filtration rates (eGFR) were exponentially integrated into the model on kdeg. Furthermore, inter-individual variability was exponentially added to all PD parameters. The concentration of free IL-6 was determined by subtracting the ziltivekimab/IL-6 complex from the total IL-6. Conclusion: The developed PK/PD model is the first to characterize the relationship between the plasma concentration of ziltivekimab and free IL-6. This innovative PK/PD model provides valuable insights and enhances the understanding of ziltivekimab’s mechanism of action, which may help to explain clinical outcomes and optimize therapeutic strategies.
Reference: PAGE 33 (2025) Abstr 11468 [www.page-meeting.org/?abstract=11468]
Poster: Drug/Disease Modelling - Infection