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.