PBPK models for the prediction of in vivo performance of oral dosage forms.
Drug absorption from the gastrointestinal (GI) tract is a highly complex process dependent upon numerous factors including the physicochemical properties of the drug, characteristics of the formulation and interplay with the underlying physiological properties of the GI tract. The ability to accurately predict oral drug absorption during drug product development is becoming more relevant given the current challenges facing the pharmaceutical industry. Physiologically-based pharmacokinetic (PBPK) modeling provides an approach that enables the plasma concentration-time profiles to be predicted from preclinical in vitro and in vivo data and can thus provide a valuable resource to support decisions at various stages of the drug development process. Whilst there have been quite a few successes with PBPK models identifying key issues in the development of new drugs in vivo, there are still many aspects that need to be addressed in order to maximize the utility of the PBPK models to predict drug absorption, including improving our understanding of conditions in the lower small intestine and colon, taking the influence of disease on GI physiology into account and further exploring the reasons behind population variability. Importantly, there is also a need to create more appropriate in vitro models for testing dosage form performance and to streamline data input from these into the PBPK models. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the current status of PBPK models available. The current challenges in PBPK set-ups for oral drug absorption including the composition of GI luminal contents, transit and hydrodynamics, permeability and intestinal wall metabolism are discussed in detail. Further, the challenges regarding the appropriate integration of results from in vitro models, such as consideration of appropriate integration/estimation of solubility and the complexity of the in vitro release and precipitation data, are also highlighted as important steps to advancing the application of PBPK models in drug development. It is expected that the "innovative" integration of in vitro data from more appropriate in vitro models and the enhancement of the GI physiology component of PBPK models, arising from the OrBiTo project, will lead to a significant enhancement in the ability of PBPK models to successfully predict oral drug absorption and advance their role in preclinical and clinical development, as well as for regulatory applications.
Institute of Pharmaceutical Technology, Goethe University, Frankfurt/Main, Germany. Electronic address: kostewicz@em.uni-frankfurt.de.
Edmund S
ES
Kostewicz
Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, United Kingdom.
Leon
L
Aarons
Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University, Sweden.
Martin
M
Bergstrand
Simulations Plus, Inc., Lancaster, CA, United States.
Michael B
MB
Bolger
Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, United Kingdom.
Aleksandra
A
Galetin
Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, United Kingdom.
Oliver
O
Hatley
Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield, United Kingdom.
Masoud
M
Jamei
Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Ware, Hertfordshire, United Kingdom.
Richard
R
Lloyd
Department of Biopharmaceutics, Pharmaceutical Sciences R&D, Sanofi, Vitry sur Seine Cedex, France.
Xavier
X
Pepin
Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, United Kingdom; Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield, United Kingdom.
Amin
A
Rostami-Hodjegan
Department of Pharmacy, Uppsala University, Uppsala, Sweden.
Erik
E
Sjögren
Medicines Evaluation CVGI, Pharmaceutical Development, AstraZeneca R&D Mölndal, Sweden.
Christer
C
Tannergren
Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield, United Kingdom.
David B
DB
Turner
Institute of Pharmaceutical Technology, Goethe University, Frankfurt/Main, Germany.
Christian
C
Wagner
Department of Biopharmaceutics, University of Greifswald, Greifswald, Germany.
Werner
W
Weitschies
Institute of Pharmaceutical Technology, Goethe University, Frankfurt/Main, Germany.
Jennifer
J
Dressman
D000284:Administration, Oral; D000818:Animals; D001702:Biopharmaceutics / Q000379:methods*; D002626:Chemistry, Pharmaceutical; D004304:Dosage Forms; D041981:Gastrointestinal Tract / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption; D008954:Models, Biological; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*; D010599:Pharmacokinetics; D012995:Solubility
D004304:Dosage Forms; D004364:Pharmaceutical Preparations
Gastrointestinal physiology; In vitro biopharmaceutical tools; Innovative Medicines Initiative (IMI); Oral Biopharmaceutical Tools (OrBiTo); Physiologically-based pharmacokinetic (PBPK) models; Predicting drug absorption