Simulating lung concentration for COVID-19 drugs
The permeability-limited lung model is particularly suitable for modeling and simulating drug disposition within the lung mass compartment and epithelial lining fluid compartment, which are the target sites for anti-viral effects. The methodology of simulating these concentrations has been applied previously to tuberculosis [14], and recently for three COVID-19 repurposed drugs [17].

PBPK simulation and comparison with observed clinical data

The predicted Cmax and AUC in healthy subjects were compared to the observed data to ensure models were suitable for their intended use. Subsequently, the predicted Cmax and AUC ratios of organ dysfunction (estimated as the ratio of predicted Cmax and AUC of organ dysfunction relative to healthy populations) were compared with the observed organ dysfunction Cmax and AUC ratios. Partition coefficients (KP) between lung tissue and plasma data were available in rats (as shown in Supplementary Table 2 ). Rat tissue KP values were compared to in silico predicted human KP values, assuming the unbound distribution is independent of species.

Sensitivity analyses with varying degrees of CYP suppression by cytokine storm

Sensitivity analysis, via Simcyp®’s sensitivity analysis tool, was performed to study the effect of AUC change with reduced CYP3A4 abundance in the liver and gut. Acalabrutinib and ibrutinib are sensitive CYP3A4 substrates, so these were chosen for this sensitivity analyses. CYP3A4 abundance was varied, with values 10 to 90% lower than those observed in healthy volunteers. Physiological differences between healthy volunteers and patients with hepatic organ impairment are shown in Supplementary Table 4.
RESULTS