IMI - oral biopharmaceutics tools project - evaluation of bottom-up PBPK prediction success part 1: Characterisation of the OrBiTo database of compounds.
Predicting oral bioavailability (Foral) is of importance for estimating systemic exposure of orally administered drugs. Physiologically-based pharmacokinetic (PBPK) modelling and simulation have been applied extensively in biopharmaceutics recently. The Oral Biopharmaceutical Tools (OrBiTo) project (Innovative Medicines Initiative) aims to develop and improve upon biopharmaceutical tools, including PBPK absorption models. A large-scale evaluation of PBPK models may be considered the first step. Here we characterise the OrBiTo active pharmaceutical ingredient (API) database for use in a large-scale simulation study. The OrBiTo database comprised 83 APIs and 1475 study arms. The database displayed a median logP of 3.60 (2.40-4.58), human blood-to-plasma ratio of 0.62 (0.57-0.71), and fraction unbound in plasma of 0.05 (0.01-0.17). The database mainly consisted of basic compounds (48.19%) and Biopharmaceutics Classification System class II compounds (55.81%). Median human intravenous clearance was 16.9L/h (interquartile range: 11.6-43.6L/h; n=23), volume of distribution was 80.8L (54.5-239L; n=23). The majority of oral formulations were immediate release (IR: 87.6%). Human Foraldisplayed a median of 0.415 (0.203-0.724; n=22) for IR formulations. The OrBiTo database was found to be largely representative of previously published datasets. 43 of the APIs were found to satisfy the minimum inclusion criteria for the simulation exercise, and many of these have significant gaps of other key parameters, which could potentially impact the interpretability of the simulation outcome. However, the OrBiTo simulation exercise represents a unique opportunity to perform a large-scale evaluation of the PBPK approach to predicting oral biopharmaceutics.
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
Simcyp Ltd., United Kingdom.
Shriram M
SM
Pathak
Simulations Plus, Inc., United States.
Michael B
MB
Bolger
University of Manchester, United Kingdom.
Leon
L
Aarons
University of Manchester, United Kingdom; Simcyp Ltd., United Kingdom.
Amin
A
Rostami-Hodjegan
AbbVie, Germany.
Jonas
J
Angstenberger
AbbVie, Germany.
Franziska
F
Graf
AbbVie, Germany.
Loic
L
Laplanche
AbbVie, Germany.
Thomas
T
Müller
AstraZeneca, Sweden.
Sara
S
Carlert
AstraZeneca, United States.
Pankaj
P
Daga
AstraZeneca, United Kingdom.
Dónal
D
Murphy
AstraZeneca, Sweden.
Christer
C
Tannergren
AstraZeneca, United Kingdom.
Mohammed
M
Yasin
Bayer Pharma AG, Germany.
Susanne
S
Greschat-Schade
Bayer Pharma AG, Germany.
Wolfgang
W
Mück
Bayer Pharma AG, Germany.
Uwe
U
Muenster
Bayer Pharma AG, Germany.
Dorina
D
van der Mey
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.
Kerstin Julia
KJ
Frank
GlaxoSmithKline, United Kingdom.
Richard
R
Lloyd
Janssen, Belgium.
Lieve
L
Adriaenssen
Janssen, Belgium.
Jan
J
Bevernage
Janssen, Belgium.
Loeckie
L
De Zwart
Janssen, Belgium.
Dominique
D
Swerts
Janssen, Belgium.
Christophe
C
Tistaert
Janssen, Belgium.
An
A
Van Den Bergh
Janssen, Belgium.
Achiel
A
Van Peer
Novartis, Switzerland.
Stefania
S
Beato
Novartis, Switzerland.
Anh-Thu
AT
Nguyen-Trung
Pfizer, United Kingdom.
Joanne
J
Bennett
Pfizer, United Kingdom.
Mark
M
McAllister
Pfizer, United Kingdom.
Mei
M
Wong
Sanofi, United States.
Patricia
P
Zane
Sanofi, France.
Céline
C
Ollier
Sanofi, France.
Pascale
P
Vicat
Sanofi, Germany.
Markus
M
Kolhmann
Sanofi, Germany.
Alexander
A
Marker
Sanofi, France.
Priscilla
P
Brun
Sanofi, France.
Florent
F
Mazuir
Sanofi, France.
Stéphane
S
Beilles
Sanofi, Germany.
Marta
M
Venczel
Sanofi, France.
Xavier
X
Boulenc
Sanofi, Germany.
Petra
P
Loos
Uppsala University, Sweden.
Hans
H
Lennernäs
AstraZeneca, Sweden.
Bertil
B
Abrahamsson
D000284:Administration, Oral; D001702:Biopharmaceutics / Q000379:methods*; D016208:Databases, Factual; 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)