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IMI – oral biopharmaceutics tools project – evaluation of bottom-up PBPK prediction success part 1: Characterisation of the OrBiTo database of compounds

2016; Elsevier BV; Volume: 96; Linguagem: Inglês

10.1016/j.ejps.2016.09.027

1879-0720

Alison Margolskee, Adam S. Darwich, Xavier Pépin, Shriram M. Pathak, Michael B. Bolger, Leon Aarons, Amin Rostami‐Hodjegan, Jonas Angstenberger, Graf F, Loïc Laplanche, Thomas Müller, Sara Carlert, Pankaj Daga, Donal B. Murphy, Christer Tannergren, Mohammed Yasin, Susanne Greschat‐Schade, Wolfgang Mück, Uwe Muenster, Dorina van der Mey, Kerstin J. Frank, Richard Lloyd, Lieve Adriaenssen, Jan Bevernage, Loeckie De Zwart, Dominique Swerts, Christophe Tistaert, An Van den Bergh, Achiel Van Peer, Stefania Beato, Anh-Thu Nguyen-Trung, Joanne Bennett, Mark McAllister, Mei Wong, Patricia Zane, Céline Ollier, Pascale Vicat, Markus Kolhmann, Alexander Marker, Priscilla Brun, Florent Mazuir, Stéphane Beilles, Márta Venczel, Xavier Boulenc, Petra Loos, Hans Lennernäs, Bertil Abrahamsson,

Analytical Chemistry and Chromatography

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 16.9 L/h (interquartile range: 11.6–43.6 L/h; n = 23), volume of distribution was 80.8 L (54.5–239 L; n = 23). The majority of oral formulations were immediate release (IR: 87.6%). Human Foral displayed 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.