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Characterization of Pharmacokinetics in the Göttingen Minipig with Reference Human Drugs: An In Vitro and In Vivo Approach

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An Erratum to this article was published on 22 August 2016

Abstract

Purpose

This study aims to expand our understanding of the mechanisms of drug absorption, distribution, metabolism and excretion in the Göttingen minipig to aid a knowledge-driven selection of the optimal species for preclinical pharmaceutical research.

Methods

The pharmacokinetics of seven reference compounds (antipyrine, atenolol, cimetidine, diazepam, hydrochlorothiazide, midazolam and theophylline) was investigated after intravenous and oral dosing in minipigs. Supportive in vitro data were generated on hepatocellularity, metabolic clearance in hepatocytes, blood cell and plasma protein binding and metabolism routes.

Results

Systemic plasma clearance for the seven drugs ranged from low (1.1 ml/min/kg, theophylline) to close to liver blood flow (37.4 ml/min/kg, cimetidine). Volume of distribution in minipigs ranged from 0.7 L/kg for antipyrine to 3.2 L/kg for hydrochlorothiazide. A gender-related difference of in vivo metabolic clearance was observed for antipyrine. The hepatocellularity for minipig was determined as 124 Mcells/g liver, similar to the values reported for human. Based on these data a preliminary in vitro to in vivo correlation (IVIVC) for metabolic clearance measured in hepatocytes was investigated. Metabolite profiles of diazepam and midazolam compared well between minipig and human.

Conclusions

The results of the present study support the use of in vitro metabolism data for the evaluation of minipig in preclinical research and safety testing.

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Abbreviations

ADME:

Absorption, distribution, metabolism and excretion

AUC:

Area under the curve

CYP:

Cytochrome P450

FCS:

Fetal calf serum

GFR:

Glomerular filtration rate

IVIVC:

In vitro-in vivo correlation

NCA:

Non-compartmental analysis

PBPK:

Physiologically-based pharmacokinetic

PK:

Pharmacokinetic

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was funded by the Roche Post-Doc Fellowship (RPF) Program. We thank all our associates for their support, in particular Anthony Vandjour, Christelle Rapp and Claudia Senn for the in vivo measurements, Hamina Daff, Sandrine Simon, Isabelle Walter, Andreas Goetschi and Pierre - Alexis Gonsard for their work on plasma protein binding and bioanalysis, Aynur Ekiciler for the hepatocellularity evaluation and in vitro intrinsic clearance determination, Peter Schrag for the blood to plasma portioning measurements, Martin Kapps for the LC/MS bioanalysis, and Michaela Marschmann for the investigation of the metabolite profiles.

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Authors and Affiliations

  1. Pharmaceutical Sciences, Roche Pharmaceutical Research and Early Development, F. Hoffmann – La Roche, Ltd, Basel, Switzerland

    Floriane Lignet, Eva Sherbetjian, Nicole Kratochwil, Russell Jones, Michael B. Otteneder, Thomas Singer & Neil Parrott

  2. Klinische Pharmakologie & Toxikologie, Universitätsspital Basel, Basel, Switzerland

    Claudia Suenderhauf

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  1. Floriane Lignet
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  2. Eva Sherbetjian
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Correspondence to Floriane Lignet.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s11095-016-2026-x.

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Lignet, F., Sherbetjian, E., Kratochwil, N. et al. Characterization of Pharmacokinetics in the Göttingen Minipig with Reference Human Drugs: An In Vitro and In Vivo Approach. Pharm Res 33, 2565–2579 (2016). https://doi.org/10.1007/s11095-016-1982-5

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