Prediction of Oral Bioavailability in silico

Authors: Lawless M, DiBella J, Bolger MB, Clark RD, Huehn E, Waldman M, Zhang J, Lukacova V
Conference: ISSX
Keywords: ADMET, F%, major clearance pathways (MCP), oral bioavailability
Software: ADMET Predictor®
Division: Simulations Plus

Abstract

  • A database of 62 drugs including oral bioavailability (F%) and dose was constructed
    • All compounds’ reported major clearance pathways (MCP) were CYP-mediated1
    • For 43 drugs with more than one reported value of F%, the average experimental CV% was 29%
  • Reported F% values2 varied from 3% (fluphenazine) to 99% (diazepam, galantamine, glimepiride, indomethacin, and tamsulosin), with an average of 60%
  • F% was predicted by integrating quantitative structure activity relationship (QSAR) model predictions3 and physiologically based pharmacokinetic (PBPK) simulations 4
    • A 35-year-old American male physiology was use for all PBPK simulations
  • All molecules were predicted to be substrates of the CYP associated with their MCP
  • In 42 of the 62 molecules, the CYP isoform with highest predicted intrinsic clearance (CLint) was the same as the MCP
  • Overall, 68% of the molecules were predicted within 2-fold of their reported F%
  • Scaling Vmax by the CYP substrate model’s confidence estimate resulted in fewer underpredictions

13th European ISSX Meeting, June 22-25, 2015, Glasgow, Scotland

By Michael Lawless, John DiBella, Michael B. Bolger, Robert D. Clark, Eva Huehn, Marvin Waldman, Jinhua Zhang, Viera Lukacova