Investigation of Low Bioavailability Using Physiologically Based Pharmacokinetic Modeling: A Case Example (Lassbio-596)

Aim: Investigate the possible mechanism (s) of the poor bioavailability of a lipophilic compound in rats using the physiologically based pharmacokinetic (PBPK) modeling approach.
Methodology: A rat PBPK model was constructed using data from intravenous administration, and verified by comparing predicted tissue concentrations (kidneys, liver and lungs) with experimental data from tissue distribution studies. Using parameter sensitivity analysis, the model was used to investigate the absorption characteristics of the compound and the probable causes of the low absorbed fraction.
Results: Sensitivity analysis of absorption parameters was performed to understand the absorption characteristic of the compound in regard to permeability, solubility and intra-gut degradation. Taking in consideration the latter factor, the oral pharmacokinetics of the tested compound was satisfactorily predicted in rats.
Conclusion: The PBPK simulation results suggest that chemical or/and bacterial degradation of the compound in the gastrointestinal tract may be a probable cause of the low bioavailability observed.