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A Physiologically Based Pharmacokinetic Model of the Minipig: Data Compilation and Model Implementation

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Abstract

In today’s pharmaceutical research and development, physiologically-based pharmacokinetic (PBPK) modeling plays an important role in the design, evaluation and interpretation of pharmacokinetic, toxicokinetic and formulation studies. PBPK models incorporate in vitro physicochemical and biochemical data in a physiologically based model framework to simulate in vivo exposure. The comparison of simulated concentrations to those measured in in vivo studies can be used to gain insights into compound behavior and to inform PBPK based human pharmacokinetic predictions. The Göttingen minipig is gaining importance as a large animal model in pharmaceutical research due to its physiological and anatomical similarities to human and is increasingly replacing dog and non-human primate in preclinical studies. However, no PBPK model for minipig has yet been published. This review discusses the information available to establish the physiological database for this species and highlights the gaps in current knowledge. A preliminary PBPK model is created from this database and simulations for two drugs dosed both intravenously and orally are compared to measured plasma concentrations. Results support the validity of the model with simulated plasma concentrations within the range of the observations. In conclusion, the model will need to be refined as additional physiological data become available, but it can already provide useful simulations to assist pharmaceutical research and development in the minipig.

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Abbreviations

ACAT:

Advanced Compartmental Absorption and Transit

BCS:

Biopharmaceutics Classification System

CO:

cardiac output

CYP:

cytochrome P450

Fabs:

fraction of dose absorbed

GFR:

glomerular filtration rate

GI:

gastrointestinal

PBPK:

physiologically based pharmacokinetic

PK:

pharmacokinetics

SEF:

surface area enhancement factor

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Acknowledgments and disclosures

This study was funded by the Roche Postdoc Fellowship (RPF) program. We thank Professor Hans Lennernas, from the University of Uppsala, and Niels-Christian Ganderup, from Ellegaard A/S, for the helpful discussion and Jens Ellegaard, from Ellegaard A/S, Denmark for providing data and access to the minipig facility

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  1. F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Non-Clinical Safety, Grenzacherstrasse 124, B70/R125, Basel, CH-4070, Switzerland

    Claudia Suenderhauf

  2. F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Non-Clinical Safety, Grenzacherstrasse 124, B70/R130, Basel, CH-4070, Switzerland

    Neil Parrott

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  1. Claudia Suenderhauf
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  2. Neil Parrott
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Correspondence to Claudia Suenderhauf.

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Suenderhauf, C., Parrott, N. A Physiologically Based Pharmacokinetic Model of the Minipig: Data Compilation and Model Implementation. Pharm Res 30, 1–15 (2013). https://doi.org/10.1007/s11095-012-0911-5

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