The Development of a Physiologically Based Pharmacokinetic (PBPK) Model of Andrographolide in Mice and Scaling it up to Rats, Dogs, and Humans
Abstract
Background: Andrographolide has a potent antiviral effect in 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.
Methods: 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 fraction of the dose absorbed that enters the enterocytes by GastroPlus®, the oral dosage of 200 mg q8h 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 an understanding of a dose-response relationship and optimization of dosage regimens of andrographolide.
Keywords: Andrographolide; COVID-19; SARS-CoV-2; partition coefficient; pharmacokinetics; physiologically based pharmacokinetic (PBPK) model.
Really interesting-thank you! Might see if I can grow some too!
Thank you so much for your interested