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.
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. Foralwas 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. Foralwas 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.
University of Manchester, United Kingdom.
Adam S
AS
Darwich
University of Manchester, United Kingdom. Electronic address: alison.margolskee@manchester.ac.uk.
Alison
A
Margolskee
AstraZeneca, United Kingdom; Sanofi, France.
Xavier
X
Pepin
University of Manchester, United Kingdom.
Leon
L
Aarons
University of Manchester, United Kingdom.
Aleksandra
A
Galetin
University of Manchester, United Kingdom; Simcyp Ltd, United Kingdom.
Amin
A
Rostami-Hodjegan
AstraZeneca, Sweden.
Sara
S
Carlert
AstraZeneca, Sweden.
Maria
M
Hammarberg
AstraZeneca, Sweden.
Constanze
C
Hilgendorf
AstraZeneca, Sweden.
Pernilla
P
Johansson
AstraZeneca, Sweden.
Eva
E
Karlsson
AstraZeneca, United Kingdom.
Dónal
D
Murphy
AstraZeneca, Sweden.
Christer
C
Tannergren
AstraZeneca, Sweden.
Helena
H
Thörn
AstraZeneca, United Kingdom.
Mohammed
M
Yasin
Sanofi, France.
Florent
F
Mazuir
Sanofi, France.
Olivier
O
Nicolas
Sanofi, Germany.
Sergej
S
Ramusovic
Sanofi, United States.
Christine
C
Xu
Simcyp Ltd, United Kingdom.
Shriram M
SM
Pathak
Orion Pharma, Finland.
Timo
T
Korjamo
AstraZeneca, United Kingdom; Orion Pharma, Finland.
Johanna
J
Laru
Orion Pharma, Finland.
Jussi
J
Malkki
Orion Pharma, Finland.
Sari
S
Pappinen
Orion Pharma, Finland.
Johanna
J
Tuunainen
Goethe University Frankfurt am Main, Germany.
Jennifer
J
Dressman
Goethe University Frankfurt am Main, Germany.
Simone
S
Hansmann
Goethe University Frankfurt am Main, Germany.
Edmund
E
Kostewicz
Novartis, United States.
Handan
H
He
Novartis, United States.
Tycho
T
Heimbach
Novartis, United States.
Fan
F
Wu
AbbVie, Germany.
Carolin
C
Hoft
AbbVie, Germany.
Yan
Y
Pang
Simulations Plus, Inc., United States.
Michael B
MB
Bolger
Simulations Plus, Inc., United States.
Eva
E
Huehn
Simulations Plus, Inc., United States.
Viera
V
Lukacova
Simulations Plus, Inc., United States.
James M
JM
Mullin
Simulations Plus, Inc., United States.
Ke X
KX
Szeto
Pfizer, United States.
Chester
C
Costales
Pfizer, United States.
Jian
J
Lin
Pfizer, United Kingdom.
Mark
M
McAllister
Pfizer, United States.
Sweta
S
Modi
Pfizer, United States.
Charles
C
Rotter
Pfizer, United Kingdom.
Manthena
M
Varma
Pfizer, United Kingdom.
Mei
M
Wong
Merck Sharp & Dohme (MSD), United Kingdom.
Amitava
A
Mitra
Janssen, Belgium.
Jan
J
Bevernage
Janssen, Belgium.
Jeike
J
Biewenga
Janssen, Belgium.
Achiel
A
Van Peer
GlaxoSmithKline, United Kingdom.
Richard
R
Lloyd
GlaxoSmithKline, United Kingdom.
Carole
C
Shardlow
Johannes Gutenberg University of Mainz, Germany.
Peter
P
Langguth
Johannes Gutenberg University of Mainz, Germany.
Irina
I
Mishenzon
Johannes Gutenberg University of Mainz, Germany.
Mai Anh
MA
Nguyen
Bristol-Myers Squibb, United Kingdom.
Jonathan
J
Brown
Uppsala University, Sweden.
Hans
H
Lennernäs
AstraZeneca, Sweden.
Bertil
B
Abrahamsson
D000284:Administration, Oral; D001702:Biopharmaceutics / Q000379:methods*; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005544:Forecasting; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000145:classification* / Q000378:metabolism*
D004364:Pharmaceutical Preparations
Physiologically-based pharmacokinetics (PBPK); absorption; biopharmaceutics; drug database; modelling and simulation (M&S); oral bioavailability (F(oral))