Discovery PBPK: How to Estimate the Expected Accuracy of ISIVB and IVIVB for New Chemical Entities

Authors: Bolger MB
Conference: Asia Pacific ISSX
Keywords: in silico, In vitro in vivo extrapolation (IVIVE), IVIVE, lead optimization, PBPK modeling, PK data, rat
Software: ADMET Predictor®, GastroPlus®
Division: Simulations Plus

Conclusions

  • PBPK modeling and simulation can be successfully used in the lead optimization phase of drug discovery.
  • Using CLloc, accurate bioavailability can be predicted for new compounds in a chemical series
  • Physicochemical property estimates in silico can be successfully used in the absence of measured input properties for new molecules
  • The approach can be used in early stage of lead optimization
    • Even with 15‐18 molecules with Rat PK data
  • ECCS models help to identify compounds with greater (primarily metabolized) or lesser (primarily renal or hepatic uptake) chance for accuracy in ISIVE and IVIVE.
  • Purely in silico estimates of absorption and first pass extraction by CYP clearance can be used to estimate bioavailability for compounds that are primarily metabolized.

The 6th Asia Pacific Regional ISSX Meeting, May 11-14, 2018, Zhejiang University in Hangzhou, China

By Michael B Bolger