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.