Abstract
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
physiologicallyâbased 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.