Results

The binding models were used to generate simulated BALF concentrations of IL-6, sIL-6R and the IL-6:sIL-6R complex for normal subjects, subjects at risk of developing ARDS, and subjects with ARDS. Each model was used to simulate concentrations from 300 virtual subjects. Complex concentrations were simulated under four conditions: without treatment, treatment with TCZ, treatment with SIL, and treatment with TCZ + SIL. Results are displayed in Figure 3.
Concentrations simulated from the virtual group of subjects without ARDS and not at risk for ARDS are represented as Normal subjects. Dashed lines capture 90% of the simulated Normal Subject with Treatment: None cases. Observed concentrations of IL-6 and IL-6R [5] are summarized and plotted as Treatment: None.
Simulation of concentrations in at-risk subjects and subjects with ARDS following no treatment (black circles), treatment with TCZ (orange circles), SIL (blue circles) and TCZ + SIL (green circles) are summarized and plotted (point:median, interval:5th-95th percentile for n=300 simulated subjects.)
IL-6 and IL-6:sIL-6R are greatly elevated in both simulated populations, while sIL-6R elevations are more modest.
With TCZ intervention, IL-6 levels are unaffected and sIL-6R is reduced somewhat below the Normal case. IL-6:sIL-6R complex only slightly decreased relative to the no-intervention case. While this is somewhat counterintuitive, IL-6 competes with TCZ for sIL-6R and IL-6 is greatly induced in at-risk (corresponding to a WHO Score of 3-4 [36]) and ARDS populations (corresponding to a WHO Score of 5-7 [36]). This idea is consistent with the findings of Swaroopa et al. [3], where APACHE II score, together with Day 1 serum IL-6 and serum-IL-8 concentrations predicted survival in ARDS patients.
With SIL intervention, sIL-6R levels are unaffected and IL-6 is greatly reduced below the Normal case. IL-6:sIL-6R complex is greatly decreased relative to the no-intervention case. Here, sIL-6R competes with SIL for IL-6 and sIL-6R is only modestly induced in at-risk and ARDS populations.
With TCZ+SIL intervention, IL-6 and sIL-6R levels are reduced below the Normal case and achieve suppression equivalent to monotherapy results for their respective targets. Interestingly, IL-6:sIL-6R complex reduction is predicted to be greater than monotherapy. This reflects sequestration of both components of the complex and the nonlinear binding equilibrium.