(T1430-05-28) Utilizing PBPK Modeling in GastroPlus to Explore the Pharmacogenetics of Gisenoside Rd

Purpose: Ginsenoside Rd, a bioactive component of Panax notoginseng, exhibits anti-inflammatory and neuroprotective properties. However, its pharmacokinetics, particularly oral absorption and metabolism, remain poorly understood. This study develops and validates a physiologically based pharmacokinetic (PBPK) model using GastroPlus to predict the absorption, distribution, metabolism, and excretion (ADME) of Ginsenoside Rd.

Methods: Physicochemical and pharmacokinetic data were collected from the literature and input into GastroPlus. An intravenous (IV) PBPK model was first developed, optimizing key parameters (log P, fraction unbound (Fu), clearance) for validation against human pharmacokinetic data. The validated IV model provided a clearance value for constructing the oral PBPK model. The oral model incorporated absorption and gut metabolism parameters and was refined to align with clinical data.

Results: The IV model was validated using data from a Phase I study in healthy Chinese participants receiving a 75 mg IV infusion. Initial predictions underestimated Cmax, but parameter refinements (log P = 2.09, Fu = 0.392%) improved model accuracy, yielding a clearance of 0.396 L/h. For oral dosing, initial simulations for a dose of 36 mg (1.2% of a total ginseng powder dose of 3g) overpredicted Cmax due to unaccounted gut metabolism. Adjusting the effective dose to 2.1 mg improved the prediction. The model was completed by adjusting gut absorption parameters to limit primary absorption in the duodenum and jejunum.

Conclusion: The validated IV PBPK model accurately predicted Ginsenoside Rd clearance. The required reduction in the Ginsenoside Rd reflects the progressive microbial gut metabolism that reduces bioavailability. Due to this process, absorption of Ginsenoside Rd is limited to the upper region of the small intestine. These findings enhance understanding of the pharmacokinetics of Ginsenoside Rd and inform formulation strategies for improved absorption.

Simulated (solid blue line) and observed (blue dots) plasma concentration vs. time curves for Ginsenoside Rd. A. Baseline IV model (75 mg, 30 min infusion). B. Final IV model. C. Baseline oral model (36 mg) using parameters from IV model. D. Oral model after adjustment of dose (0.7 mg). E. Final oral model after adjustment of regional absorption and dose (2.1 mg)