Uncovering the impact of COVID-19-mediated bidirectional dysregulation of cytochrome P450 3A4 on systemic and pulmonary drug concentrations using physiologically based pharmacokinetic modeling.

Abstract

Several clinical studies have shown that COVID-19 increases the systemic concentration of drugs in hospitalized patients with COVID-19. However, it is unclear how COVID-19-mediated bidirectional dysregulation of hepatic and pulmonary cytochrome P450 (CYP) 3A4 affects drug concentrations, especially in the lung tissue, which is most affected by the disease. Herein, physiologically based pharmacokinetic modeling was used to demonstrate the differences in systemic and pulmonary concentrations of 4 respiratory infectious disease drugs when CYP3A4 is concurrently downregulated in the liver and upregulated in the lung based on existing clinical data on COVID-19-CYP3A4 interactions at varying severity levels including outpatients, non-intensive care unit (ICU), and ICU patients. The study showed that hepatic metabolism is the primary determinant of both systemic and pulmonary drug concentrations despite the concurrent bidirectional dysregulation of liver and lung CYP3A4. ICU patients had the most systemic and pulmonary drug exposure, with a percentage increase in the area under the concentration-time curve in the plasma compartment of approximately 44%, 56%, 114%, and 196% for clarithromycin, nirmatrelvir, dexamethasone, and itraconazole, respectively, relative to the healthy group. Within the ICU cohort, clarithromycin exhibited its highest exposure in lung tissue mass with a fold change of 1189, whereas nirmatrelvir and dexamethasone showed their highest exposure in the plasma compartment, with fold changes of about 126 and 5, respectively, compared with the maximum therapeutic concentrations for their target pathogens. Itraconazole was significantly underexposed in the lung fluid compartment, potentially explaining its limited efficacy for the treatment of COVID-19. These findings underscore the importance of optimizing dosing regimens in at risk ICU patients to enhance both efficacy and safety profiles. SIGNIFICANCE STATEMENT: This study investigated whether COVID-19-mediated concurrent hepatic downregulation and pulmonary upregulation of cytochrome P450 (CYP) 3A4 leads to differences in the systemic and pulmonary concentrations of 4 respiratory medicines. The study demonstrated that intercompartmental differences in drug concentrations were driven by only hepatic CYP3A4 expression. This work suggests that ICU patients with significant COVID-19-CYP3A4 interactions may be at risk of clinically relevant COVID-19-drug interactions, highlighting the need for optimizing dosing regimens in this patient group to improve safety and efficacy.