Parameter Analysis for PBPK Model for Enalapril

Physiologically based pharmacokinetic (PBPK) modeling is valuable for drug development (Phase I). While PBPK models may share similar compartmental structures (e.g., blood, liver) for different species, a distinct set of physiological (e.g. compartmental volume and blood flow rate) and drug-specific (e.g. metabolism and clearance rates) parameters need to be used in different species. However, it is still difficult to obtain some of these parameters from in vivo or in vitro experiments. Hence, to predict and verify the effect and accuracy of those parameters through parameter analysis is often the only choice.

In this work we investigate the clearance PBPK model of Enalapril, a hypertensive pro-drug hydrolyzed to Enalaprilat, which is an Angiotensin Converting Enzyme (ACE) inhibitor that prevents ACE from transforming angiotensin I into angiotensin II. We extrapolate a validated PBPK model of Enalapril from the rat hepatic system to human beings. At first, we list all physiological and pharmacological parameters used in the system and justify whether a parameter extrapolation is qualified. Then, we use a parameter analysis method (Latin Hypercube that probes 1/10 to 10 fold of a predicted parameter) for those parameters, which are not obvious and may impose a direct effect on the model (e.g., metabolism/biliary clearance rate). Furthermore, we use the Monte-Carlo Method to simulate the time course of enalapril from 100 virtual subjects, which illustrate the range of PK profiles in humans.

The models are developed in Matlab, and also CellML/OpenCOR. The simulation results are compared with published data from clinical trials. In conclusion, a population PBPK model for humans has been extrapolated from a rat PBPK model for Enalapril. The physiological and PK parameters have been re-adjusted to yield the clearance ratio in humans, which is similar between these two species despite the drastic weight difference (the weight of the human is almost 250 times that of the rat).