Pharmacokinetics under the COVID-19 storm
Venkatesh Pilla Reddy1,2, Eman El-Khateeb3,4, Heeseung Jo1
1Modelling & Simulation, Early Oncology, R&D Oncology, AstraZeneca, Cambridge, UK.
British Journal of Clinical Pharmacology
|November 23, 2020
Summary
Physiologically based pharmacokinetic models assessed COVID-19 drug exposure in diverse populations. Findings support broader patient recruitment by verifying drug safety and efficacy across different groups, including those with organ impairment.
Area of Science:
- Pharmacology and Clinical Pharmacy
- Drug Development and Regulatory Science
- Infectious Diseases and Virology
Background:
- COVID-19 necessitated unconventional clinical trial designs, including relaxed exclusion criteria.
- Ensuring diverse participant representation while preventing harmful drug exposure is a critical challenge.
- Understanding factors influencing drug disposition in various populations is essential for safe and effective trial conduct.
Purpose of the Study:
- To establish a knowledge base on how intrinsic and extrinsic factors affect the disposition of repurposed COVID-19 drugs.
- To evaluate the pharmacokinetic profiles of repurposed drugs in geriatric patients, different racial groups, and individuals with organ impairment.
- To assess the risk of drug-drug interactions (DDIs) and predict drug exposure in the epithelial lining fluid (ELF) of COVID-19 patients.
Main Methods:
- Physiologically based pharmacokinetic (PBPK) modeling was employed to simulate drug disposition.
- PBPK models were used to analyze changes in pharmacokinetics (PK) across various demographic and clinical subgroups.
- Simulations predicted epithelial lining fluid (ELF) exposure under conditions of elevated cytokine levels relevant to COVID-19.
Main Results:
- Simulated PK profiles indicated no dose adjustments needed for age or race for most COVID-19 repurposed drugs.
- Dose adjustments may be necessary for patients with hepatic or renal impairment.
- PBPK simulations showed adequate ELF exposure for most drugs, with exceptions including hydroxychloroquine, azithromycin, atazanavir, and lopinavir/ritonavir.
Conclusions:
- Systematically collated data (ADME, PK parameters, DDIs, organ impairment) can validate simulated drug exposure, supporting broader patient recruitment.
- The developed PBPK model effectively assessed the impact of age and ethnicity on PK of repurposed drugs.
- The study correlated lung exposure with in vitro potency against SARS-CoV-2, aiding in drug selection and trial design.
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