Employing PBPK Modeling to Investigate COVID-19 Mediated Drug Interactions

Several clinical studies have documented COVID-19-mediated interactions with CYP3A4 substrate drugs in hospitalized patients, showing that COVID-19 reduces CYP3A4 activity in the liver and/or gut. In contrast, our findings reveal that SARS-CoV-2 infection upregulates CYP3A4 expression in Vero E6 cells, has no impact on CYP3A4 in postmortem COVID-19 human lung tissues, and upregulates it in the nasopharyngeal swabs of non-ICU hospitalized COVID-19 patients. These observations suggest that SARS-CoV-2 infection causes a tissue-specific, bidirectional dysregulation of CYP3A4, potentially leading to varying drug concentrations across different body compartments. Therefore, it is important to demonstrate how COVID-19-mediated bidirectional dysregulation of CYP3A4 will affect intercompartmental drug concentrations and therapeutic outcomes.
Using physiologically based pharmacokinetic (PBPK) modeling, this study investigated the impact of the concurrent hepatic downregulation and pulmonary upregulation of CYP3A4 using hepatic and respiratory COVID-19 - CYP3A4 interactions data in COVID-19 patients with different disease severity including outpatients, non-ICU, and ICU hospitalized patients. The PBPK model was performed using Simcyp version 22.1, with virtual participants categorized into healthy individuals and COVID-19 patients, comprising outpatients, non-ICU, and ICU hospitalized patients. The only physiological parameter altered in these patient cohorts was the CYP3A4 enzyme levels in the liver and lungs, based on relevant clinical data. The multicompartment permeability-limited lung model was activated to incorporate lung CYP3A4 metabolism, without modifying any other lung parameters. The model was then simulated with four CYP3A4 substrate drugs commonly used to treat respiratory infections—nirmatrelvir/ritonavir, dexamethasone, clarithromycin, and itraconazole. The resulting systemic and pulmonary PK profiles of these drugs were compared to the effective concentrations needed to achieve the desired pharmacological effect against their respective respiratory pathogens. Additionally, the study assessed how this bidirectional dysregulation of CYP3A4 influences systemic and pulmonary drug distribution.
The study findings demonstrated that hepatic CYP3A4 metabolism plays a central role in determining both systemic and pulmonary drug concentrations, even when lung CYP3A4 is upregulated. This suggests that hepatic CYP3A4 metabolism is likely more crucial for optimizing dosing in COVID-19 patients who are at risk of disease-drug interactions. Overall, ICU patients experienced the greatest systemic and pulmonary drug overexposure, consistent with the significant downregulation of hepatic CYP3A4. For example, compared to healthy individuals, ICU patients had the highest AUCplasma increase of about 196%, 114%, 56%, and 44% for itraconazole, dexamethasone, nirmatrelvir, and clarithromycin, respectively. Relative to the optimal therapeutic concentrations for their respective pathogens, nirmatrelvir and dexamethasone had their highest overexposure in the plasma compartment with fold changes of approximately 126 and 5, respectively, while clarithromycin was overexposed in the lung tissue mass compartment with a fold change of 1189. Notably, itraconazole was substantially underexposed in the lung fluid compartment, which may partly account for its limited effectiveness in treating SARS-CoV-2 infection.
This study have demonstrated that PBPK modeling can be used to investigate the impact of disease-drug interactions across different body compartments to inform the design of dosing regimens that achieves optimal therapeutic concentrations at the target site of action and beyond.