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.