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

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• 作者：Alison Margolskee^a ; ^{alison.margolskee@manchester.ac.uk} ; Adam S. Darwich^a ; Xavier Pepin^b ; ^c ; Shriram M. Pathak^d ; Michael B. Bolger^e ; Leon Aarons^a ; Amin Rostami-Hodjegan^a ; ^d ; Jonas Angstenberger^f ; Franziska Graf^f ; Loic Laplanche^f ; Thomas Mü ; ller^f ; Sara Carlert^g ; Pankaj Daga^h ; Dó ; nal Murphy^b ; Christer Tannergren^g ; Mohammed Yasin^b ; Susanne Greschat-Schadeⁱ ; Wolfgang Mü ; ckⁱ ; Uwe Muensterⁱ ; Dorina van der Meyⁱ ; Kerstin Julia Frank^j ; Richard Lloyd^k ; Lieve Adriaenssen^l ; Jan Bevernage^l ; Loeckie De Zwart^l ; Dominique Swerts^l ; Christophe Tistaert^l ; An Van Den Bergh^l ; Achiel Van Peer^l ; Stefania Beato^m ; Anh-Thu Nguyen-Trung^m ; Joanne Bennettⁿ ; Mark McAllisterⁿ ; Mei Wongⁿ ; Patricia Zane^o ; Cé ; line Ollier^c ; Pascale Vicat^c ; Markus Kolhmann^p ; Alexander Marker^p ; Priscilla Brun^c ; Florent Mazuir^c ; Sté ; phane Beilles^c ; Marta Venczel^p ; Xavier Boulenc^c ; Petra Loos^p ; Hans Lennern&auml ; s^q ; Bertil Abrahamsson^g
• 关键词：API ; active pharmaceutical ingredient ; AUC ; area under the curve ; BCS ; biopharmaceutics classification system ; BP ; blood-to-plasma ratio ; Cmax ; maximum concentration ; CL ; clearance ; Do ; dose number according to BCS ; DDI ; drug-drug interaction ; EFPIA ; European Federation of Pharmaceutical Industries and Associations ; Foral ; absolute oral bioavailability ; Frel ; relative bioavailability ; fup ; fraction unbound in plasma ; IMI ; Innovative Medicines Initiative ; LogP ; logarithm of the octanol/water part
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2017
• 出版时间：1 January 2017
• 年：2017
• 卷：96
• 期：Complete
• 页码：598-609
• 全文大小：1099 K
• 卷排序：96

文摘

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.