Aims: The storm-like nature of the health crises caused by COVID-19 has led to unconventional clinical trial practices such as the relaxation of exclusion criteria. The question remains: how can we conduct diverse trials without exposing sub-groups of populations to potentially higher drug exposure levels? The aim of this study was to build an extensive knowledge-base of the effect of intrinsic and extrinsic factors on the disposition of several repurposed COVID-19 drugs. Methods: Verified physiologically‐based pharmacokinetic (PBPK) models were used study the effect of COVID-19 drugs PK in geriatric patients, race, organ impairment, DDI risks, disease-drug interaction for repurposed COVID-19 drugs. Furthermore, these models were used to predict epithelial lining fluid (ELF) exposure which is relevant for COVID-19 patients by accounting for the interplay between cytokines and metabolic disposition. Results: The simulated PK profiles suggest no dose adjustments are required based on age and race for COVID-19 drugs; however, sometimes dose adjustments are warranted for patients exhibiting hepatic/renal impairment in addition to COVID-19 co-morbidity. PBPK model simulations suggest ELF exposure to attain a target concentration was adequate for most drugs except azithromycin, atazanavir and lopinavir/ritonavir. Conclusion: We demonstrate that systematically collated data on the ADME, human PK parameters, DDIs, and organ impairment has enabled verification of simulated plasma and lung tissue exposure of many repurposed COVID-19 drugs to justify broader recruitment criteria for patients. In addition, developed PBPK model helped to assess the correlation between target site exposure to relevant potency values from in vitro studies for SARS-CoV-2.