Purpose <p>Recent studies have demonstrated the potent antiviral activity of pyronaridine against severe acute respiratory syndrome coronavirus 2 (SARS−CoV−2), highlighting the potential for repurposing Pyramax^® (a fixed-dose combination of pyronaridine/artesunate), an approved antimalarial therapy, for COVID−19 treatment.</p> Methods <p>We developed a physiologically based pharmacokinetic (PBPK) model for pyronaridine using multispecies (hamster, rat, dog, and human) PK data, validated with preclinical data, literature-based healthy subject PK data, and sparse plasma concentration data from COVID−19 patients. Human PK parameters were optimized for both healthy and COVID−19 populations to account for disease-related physiological changes.</p> Results <p>The pyronaridine concentrations in the respiratory tissues were predicted in the patient populations and compared to the reported IC₅₀ values ranging (373.0 to 559.5) µg/L for SARS−CoV−2 inhibition to predict the potential efficacy of drugs. Pyronaridine was substantially distributed in respiratory tissues, with lung- and trachea-to-blood concentration ratios of (29 and 14)–fold, respectively. The trough plasma concentration to in vitro IC₅₀ ratios (C_trough-to-IC₅₀ ratios) in lung and trachea were respectively (4.11 ± 0.44) and (1.96 ± 0.21) against the lower IC₅₀ threshold, and (2.74 ± 0.29) and (1.31 ± 0.14) against the upper threshold. Pyronaridine concentrations were maintained above the IC₅₀ values for approximately 13−19 days in the lung, and 2−7 days in the trachea after the last dosing, suggesting extended antiviral efficacy beyond the treatment period.</p> Conclusion <p>This study addressed previous modeling limitations relying on PK data from healthy subjects by applying PK data from COVID−19 patients to model development and validation. These results support the potential antiviral effects of pyronaridine in COVID−19 patients through PBPK modeling and provide a basis for future clinical trials.</p>