IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 3: Identifying gaps in system parameters by analysing In Silico performance across different compound classes

Research output: Contribution to journalArticle

  • External authors:
  • Alison Margolskee
  • Xavier Pepin
  • Sara Carlert
  • Maria Hammarberg
  • Constanze Hilgendorf
  • Pernilla Johansson
  • Eva Karlsson
  • Donal Murphy
  • Christer Tannergren
  • Helena Thorn
  • Mohammed Yasin
  • Florent Mazuir
  • Olivier Nicolas
  • Sergej Ramusovic
  • Christine Xu
  • Shriram Pathak
  • Timo Korjamo
  • Johanna Laru
  • Jussi Malkki
  • Sari Pappinen
  • Johanna Tuunainen
  • Jennifer Dressman
  • Simone Hansmann
  • Edmund S. Kostewicz
  • Handan He
  • Tycho Heimbach
  • Fan Wu
  • Carolin Hoft
  • Yan Pang
  • Michael Bolger
  • Eva Huehn
  • Tycho Heimbach
  • Fan Wu
  • Carolin Hoft
  • Yan Pang
  • Michael B. Bolger
  • Eva Huehn
  • Viera Lukacova
  • James M. Mullin
  • Ke X. Szeto
  • Chester Costales
  • Jian Lin
  • Mark McAllister
  • Sweta Modi
  • Charles Rotter
  • Manthena Varma
  • Mei Wong
  • Amitava Mitra
  • Jan Bevernage
  • Jeike Biewenga
  • Achiel Van Peer
  • Richard Lloyd
  • Carole Shardlow
  • Peter Langguth
  • Irina Mishenzon
  • Mai Anh Nguyen
  • Jonathan Brown
  • Hans Lennerans
  • Bertil Abrahmsson


Three Physiologically Based Pharmacokinetic software packages (GI-Sim, Simcyp® Simulator, and GastroPlus™) were evaluated as part of the Innovative Medicine Initiative Oral Biopharmaceutics Tools project (OrBiTo) during a blinded “bottom-up” anticipation of human pharmacokinetics. After data analysis of the predicted vs. measured pharmacokinetics parameters, it was found that oral bioavailability (Foral) was underpredicted for compounds with low permeability, suggesting improper estimates of intestinal surface area, colonic absorption and/or lack of intestinal transporter information. Foral was also underpredicted for acidic compounds, suggesting overestimation of impact of ionisation on permeation, lack of information on intestinal transporters, or underestimation of solubilisation of weak acids due to less than optimal intestinal model pH settings or underestimation of bile micelle contribution. Foral was overpredicted for weak bases, suggesting inadequate models for precipitation or lack of in vitro precipitation information to build informed models. Relative bioavailability was underpredicted for both high logP compounds as well as poorly water-soluble compounds, suggesting inadequate models for solubility/dissolution, underperforming bile enhancement models and/or lack of biorelevant solubility measurements. These results indicate areas for improvement in model software, modelling approaches, and generation of applicable input data.

However, caution is required when interpreting the impact of drug-specific properties in this exercise, as the availability of input parameters was heterogeneous and highly variable, and the modellers generally used the data “as is” in this blinded bottom-up prediction approach.

Bibliographical metadata

Original languageEnglish
Pages (from-to)626-642
Number of pages17
JournalEuropean Journal of Pharmaceutical Sciences
Early online date28 Sep 2016
Publication statusPublished - 1 Jan 2017

Related information


View all