Development of Physiologically-Based Pharmacokinetic (PBPK) Model for Andrographolide

Abstract

The coronavirus disease 2019 (COVID-19) that is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become an urgent crisis of global health. Andrographolide is a major natural compound found in a Thai plant namely Andrographis paniculata (Burm.f.) Wall. Ex. Nees. This phytochemical has been demonstrated a potent antiviral effect for COVID-19 treatment. A present, the in vivo studies of andrographolide regarding the anti-SASR-CoV-2 effect are still invisible. The purpose of this study was to develop a physiologically based pharmacokinetic (PBPK) animal model using available published data. Additionally, the model was further scaled up to humans to predict andrographolide concentrations in the lungs. This is significant because it may be critical to demonstrate an appropriate dosage regimen of andrographolide for COVID-19 treatment. The developed PBPK model with perfusion-limited assumption comprised of five tissue compartments including lung, liver, fat, slowly perfused organ and rapidly perfused organ. The feature of the developed PBPK model was integrating hepatic UGT2B7-mediated metabolism in the mouse liver. The Michaelis-Menten equation with the extrapolated maximum velocity of 626.5 mmol/h was used to describe the metabolism in humans. The saturation of the metabolism occurred after multiple oral receiving 12 g q 8 h of andrographolide that could not be used therapeutically. Using Monte Carlo simulation, most of the simulated subjects who orally receiving of 200 mg q 8 h andrographolide could provide a free drug 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, the toxicity did not occur at the therapeutic dosage. Once additional data, the PBPK would be needed to recalibrate to gain understanding in a dose-response relationship and optimization of dosage regimens of andrographolide. Last, our developed model also featured a preliminary assess the possible herb-drug interaction based on the EMA guideline and the US FDA criteria. The model predicted could imply that the possible interaction caused by andrographolide is unlikely to appear after multiple oral administrations of 1400 mg.

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