Risk Assessment For Drug Degradation Products Using Physiologically Based Pharmacokinetic Models

Intestinal permeability was predicted using a set of related compound data to correlate measured Caco-2 permeability with molecular descriptors by multivariate regression. Sensitivity analyses were conducted to evaluate the impact of PBPK model parameters on plasma level predictions. To evaluate patient population effects on exposure profiles, the PBPK model parameters were varied in meaningful ways using Monte Carlo methods. Based on population PBPK models, distributions of target tissue exposure in rats and humans were simulated and compared to derive human safe dose. As results, rat PBPK model-predicted aniline concentration time profiles were in reasonable agreement with published profiles. Distributions of target tissue exposure in rats and humans were generated and compared based on a criterion. A human reference dose was then selected at a value of 1% criteria. This approach was compared to traditional risk assessment calculations. In conclusion, the PBPK modeling approach resulted in drug degradation product risk specifications that were less stringent than those estimated by conventional risk assessment approach. The PBPK modeling approach provides a rational basis for drug instability risk assessment by focusing on target tissue exposure and leveraging physiological, biochemical, biophysical knowledge of compounds and species.