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