What question did this study set out to answer?

The aim is to select the first-in-human dose for SYHA1805 and validate pharmacokinetics using predictive models.

July 18, 2026Pharmaceutics0 citationsOpen Access

First-in-Human Dose Selection, Pharmacokinetics Prediction, and Clinical Validation of SYHA1805, a Novel FXR Agonist, Using Allometric Scaling and PBPK Modeling

Key Points

The aim is to select the first-in-human dose for SYHA1805 and validate pharmacokinetics using predictive models.
Integrated in vitro and in vivo ADME and toxicological characterizations were performed.
Allometric scaling used monkeys and rats for predictions.
PBPK modeling guided single ascending dose administration from 30 mg to 3000 mg.
Predicted human intravenous clearance of 20.7 L/h and volume of distribution of 15.1 L.
Effective dose proposal at 1150 mg supported by body surface area and exposure-based modeling.
Model simulations validated with clinical trial data from SAD study (CTR20202354).

Abstract

Background: SYHA1805 is a potent farnesoid X receptor (FXR) agonist currently in development for Metabolic Dysfunction-Associated Steatohepatitis (MASH). Methods: To determine the first-in-human (FIH) dose and guide its clinical development, an integrated approach combining in vitro and in vivo ADME and toxicological characterizations, cross-species allometric scaling (AS), and physiologically based pharmacokinetic (PBPK) modeling was employed. Results: Using monkeys and rats as extrapolation species, AS predicted a human intravenous clearance of 20.7 L/h and a steady-state volume of distribution of 15.1 L. Based on body surface area and exposure-based modeling, an FIH dosing regimen for single-dose administration was proposed, ranging from a 30 mg starting dose to a 3000 mg maximum, with an effective dose of 1150 mg. These dosing strategies were further supported by PBPK models, which accurately estimated human systemic exposure. The model simulations were subsequently validated by clinical trial data from a single ascending dose (SAD) study (CTR20202354). Conclusions: These findings establish a robust pharmacokinetic foundation for the continued clinical advancement of SYHA1805.

问 AI

Bookmark

View Full Paper