IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 2: An introduction to the simulation exercise and overview of results.
Orally administered drugs are subject to a number of barriers impacting bioavailability (Foral), causing challenges during drug and formulation development. Physiologically-based pharmacokinetic (PBPK) modelling can help during drug and formulation development by providing quantitative predictions through a systems approach. The performance of three available PBPK software packages (GI-Sim, Simcyp®, and GastroPlus™) were evaluated by comparing simulated and observed pharmacokinetic (PK) parameters. Since the availability of input parameters was heterogeneous and highly variable, caution is required when interpreting the results of this exercise. Additionally, this prospective simulation exercise may not be representative of prospective modelling in industry, as API information was limited to sparse details. 43 active pharmaceutical ingredients (APIs) from the OrBiTo database were selected for the exercise. Over 4000 simulation output files were generated, representing over 2550 study arm-institution-software combinations and approximately 600 human clinical study arms simulated with overlap. 84% of the simulated study arms represented administration of immediate release formulations, 11% prolonged or delayed release, and 5% intravenous (i.v.). Higher percentages of i.v. predicted area under the curve (AUC) were within two-fold of observed (52.9%) compared to per oral (p.o.) (37.2%), however, Foraland relative AUC (Frel) between p.o. formulations and solutions were generally well predicted (64.7% and 75.0%). Predictive performance declined progressing from i.v. to solution and immediate release tablet, indicating the compounding error with each layer of complexity. Overall performance was comparable to previous large-scale evaluations. A general overprediction of AUC was observed with average fold error (AFE) of 1.56 over all simulations. AFE ranged from 0.0361 to 64.0 across the 43 APIs, with 25 showing overpredictions. Discrepancies between software packages were observed for a few APIs, the largest being 606, 171, and 81.7-fold differences in AFE between SimCYP and GI-Sim, however average performance was relatively consistent across the three software platforms.
University of Manchester, United Kingdom. Electronic address: alison.margolskee@manchester.ac.uk.
Alison
A
Margolskee
University of Manchester, United Kingdom.
Adam S
AS
Darwich
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.
Loic
L
Laplanche
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 / Q000378:metabolism*
D004364:Pharmaceutical Preparations
Absorption; Biopharmaceutics; Drug database; Modelling and simulation (M&S); Oral bioavailability (F(oral)); Physiologically-based pharmacokinetics (PBPK)