Characterisation of intravenous pharmacokinetics in Göttingen minipig and clearance prediction using established in vitro to in vivo extrapolation methodologies
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Characterisation of intravenous pharmacokinetics in Göttingen minipig and clearance prediction using established in vitro to in vivo extrapolation methodologies. / Langthaler, K; Jones, C R; Christensen, R B; Eneberg, E; Brodin, B; Bundgaard, C.
In: Xenobiotica, Vol. 52, No. 6, 2022, p. 591-607.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Characterisation of intravenous pharmacokinetics in Göttingen minipig and clearance prediction using established in vitro to in vivo extrapolation methodologies
AU - Langthaler, K
AU - Jones, C R
AU - Christensen, R B
AU - Eneberg, E
AU - Brodin, B
AU - Bundgaard, C
PY - 2022
Y1 - 2022
N2 - 1. The use of the Göttingen minipig as an animal model for drug safety testing and prediction of human pharmacokinetics (PK) continues to gain momentum in pharmaceutical research and development. The aim of this study was to evaluate in vitro to in vivo extrapolation (IVIVE) methodologies for prediction of hepatic, metabolic clearance (CL hep,met) in Göttingen minipig, using a comprehensive set of compounds. 2. In vivo clearance was determined in Göttingen minipig by intravenous cassette dosing and hepatocyte intrinsic clearance, plasma protein binding and non-specific incubation binding were determined in vitro. Prediction of CL hep,met was performed by IVIVE using conventional and adapted formats of the well-stirred liver model.3. The best prediction of in vivo CL hep,met from scaled in vitro kinetic data was achieved using an empirical correction factor based on a 'regression offset' of the IVIV relationship.4. In summary, these results expand the in vitro and in vivo PK knowledge in Göttingen minipig. We show regression corrected IVIVE provides superior prediction of in vivo CL hep,met in minipig offering a practical, unified scaling approach to address systematic under-predictions. Finally, we propose a reference set for researchers to establish their own 'lab-specific' regression correction for IVIVE in minipig.
AB - 1. The use of the Göttingen minipig as an animal model for drug safety testing and prediction of human pharmacokinetics (PK) continues to gain momentum in pharmaceutical research and development. The aim of this study was to evaluate in vitro to in vivo extrapolation (IVIVE) methodologies for prediction of hepatic, metabolic clearance (CL hep,met) in Göttingen minipig, using a comprehensive set of compounds. 2. In vivo clearance was determined in Göttingen minipig by intravenous cassette dosing and hepatocyte intrinsic clearance, plasma protein binding and non-specific incubation binding were determined in vitro. Prediction of CL hep,met was performed by IVIVE using conventional and adapted formats of the well-stirred liver model.3. The best prediction of in vivo CL hep,met from scaled in vitro kinetic data was achieved using an empirical correction factor based on a 'regression offset' of the IVIV relationship.4. In summary, these results expand the in vitro and in vivo PK knowledge in Göttingen minipig. We show regression corrected IVIVE provides superior prediction of in vivo CL hep,met in minipig offering a practical, unified scaling approach to address systematic under-predictions. Finally, we propose a reference set for researchers to establish their own 'lab-specific' regression correction for IVIVE in minipig.
U2 - 10.1080/00498254.2022.2115425
DO - 10.1080/00498254.2022.2115425
M3 - Journal article
C2 - 36000364
VL - 52
SP - 591
EP - 607
JO - Xenobiotica
JF - Xenobiotica
SN - 0049-8254
IS - 6
ER -
ID: 317732257