Effect of organ dysfunction on PK of repurposed COVID-19
drugs
The role of cytokines on the disposition of anti-cancer and rheumatoid
arthritis drugs is well understood; however, this this has not been
evaluated in COVID-19 patients. Figure 3 and Table 3show how hepatic impairment resulting from cirrhosis and renal
impairment, change the exposure levels of these repurposed drugs. The
absolute expression of CYP3A levels in severe cirrhotic subjects is
assumed to be the same as in COVID-19 patients (seeSupplementary Tables 4 and 5 for physiological differences
between Healthy population and either liver cirrhosis or renal
impairment populations within Simcyp PBPK Simulator V19). The exposure
of azithromycin, atazanavir, acalabrutinib, ruxolitinib, and
dexamethasone was clearly higher in severe hepatic impairment
(Figure 3A ) relative to healthy volunteers, suggesting the need
for dose adjustment. In case of renal impairment (Figure 3B) ,
ruxolitinib, atazanavir and azithromycin plasma exposures were
remarkably higher in severe conditions relative to healthy population.
Comparing predicted AUCR (AUC0-∞ in hepatic
impairment/AUC0-∞ in healthy volunteers) with their
corresponding observed values (whenever available) shows consistency
within 2-fold of observed data for all drugs.