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Several clinical studies have shown that COVID-19 increases the systemic concentration of drugs in hospitalized COVID-19 patients. However, it is unclear how COVID-19-mediated bidirectional dysregulation of hepatic and pulmonary CYP3A4 impacts drug concentrations, especially in the lung tissue which is most affected by the disease. Herein, PBPK modeling was used to demonstrate the differences in systemic and pulmonary concentrations of four 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-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 AUC 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, while nirmatrelvir and dexamethasone showed their highest exposure in the plasma compartment, with fold changes of about 126 and 5, respectively, compared to the maximum therapeutic concentrations for their target pathogens. Itraconazole was significantly under-exposed 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. This study investigated whether COVID-19-mediated concurrent hepatic downregulation and pulmonary upregulation of CYP3A4 leads to differences in the systemic and pulmonary concentrations of four 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.