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BACKGROUND Andrographolide has a potent antiviral effect for the treatment of coronavirus disease (COVID-19). However, there are no in vivo studies of andrographolide as an anti-COVID-19 treatment. OBJECTIVE The study aims to develop a physiologically based pharmacokinetic (PBPK) animal model and scale it up to a human model to predict andrographolide concentrations in the lungs. METHOD ADAPT5 (version 5.0.58) was used to establish the PBPK model based on 24 enrolled pharmacokinetic studies. RESULTS The perfusion limited PBPK model was developed in mice and extrapolated to rats, dogs, and humans. The metabolism of andrographolide in humans was described by the Michaelis-Menten equation. The saturation of the metabolism occurred at a high dose (12 g), which could not be used therapeutically. The optimized oral bioavailability in humans was 6.3%. Due to the limit of solubility, the dose-dependent absorption between 20-1000 mg was predicted by GastroPlus®. Using the extrapolated human PBPK model together with the predicted dose-dependent of a fraction of the dose absorbed that enters the enterocytes by GastroPlus®, the oral dosage of 200 mg q 8 h of andrographolide would provide a trough level of free andrographolide at a steady state over the reported IC50 value against SARS-CoV-2 in the lungs for the majority of healthy humans. Based on the reported CC50 value, toxicity might not occur at the therapeutic dosage. CONCLUSION The PBPK model of andrographolide in animals and humans was successfully constructed. Once additional data is available, the model would be needed to recalibrate to gain understanding in a dose-response relationship and optimization of dosage regimens of andrographolide.