From Pre-clinical to Human—Prediction of Oral Absorption and Drug-drug Interaction Potential Using Physiologically-based Pharmacokinetic (PBPK) Modeling Approach in an Industrial Setting: A Workflow by Using Case Example

A case example is presented in which the physiologically based modeling approach has been used to model the absorption of a lipophilic BCS Class II compound predominantly metabolized by CYP3A4, and to assess the interplay of absorption related parameters with the drug-drug interaction (DDI) potential.
The PBPK model was built in the rat using Gastroplus® to study the absorption characteristics of the compound. Subsequently relevant model parameters were used to predict the non-linear human PK observed during first-in-human study after optimizing the absorption model for colonic absorption, bile micelle solubilization and unbound fraction in gut enterocytes (fu_gut) using SIMCYP® simulator. The model fitted absorption parameters were then used to assess the drug-drug interaction (DDI) potential of the test compound when administered along with multiple doses of a potent CYP 3A4 inhibitor, ketoconazole. The impact of fu_gut in the extent of DDI was assessed using parameter sensitivity analysis.
After optimizing the preclinical model and taking into consideration bile micelle solubilization and colonic absorption, the non-linear pharmacokinetics of the test compound was satisfactorily predicted in man. Sensitivity analysis performed with the absorption parameter fu_gut indicated that it could be an important parameter in predicting oral absorption. In addition, DDI simulations using SIMCYP® suggest that C_max and AUC ratios may also be sensitive to the fu_gut input in the model. Since fu_gut cannot be measured experimentally, sensitivity analysis may help in assessing the importance of fu_gut in human PK and DDI prediction using SIMCYP®.