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Subcutaneous Site-of-Absorption Study with the Monoclonal Antibody Tocilizumab in Minipigs: Administration Behind Ear Translates Best to Humans

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Abstract

Minipigs have been proposed as animal model to study the subcutaneous (SC) absorption of monoclonal antibodies (mAb), because they are more translatable to humans than other species. However, the minipig SC tissue structure differs markedly depending on its location. This study explored different SC administration sites for mAb SC administration, to explore which site translates best to humans. The study assessed the SC absorption of tocilizumab (Actemra®) following administration at several injection sites: Inguinal area, flank, caudal to the ear, and interscapular area, in comparison with an IV group. After SC administration, tocilizumab absorption was most rapid from the inguinal administration site, and slowest after administration behind the ear, with absorption from the other sites in between. Tocilizumab bioavailability was 98.6, 88.3, 74.1, and 86.3% after administration in inguinal area, flank, behind the ear, and interscapular area, as determined by non-compartmental analysis. Fitting of a single first-order absorption rate constant by compartmental analysis was dissatisfactory. A combined fitting of all data was done assuming two different kinds of SC depots, one undergoing fast absorption, the other undergoing a slower absorption. The split between these absorption depots differed across administration sites, with absorption from “fast depot” in inguinal area > flank > interscapular area > behind the ear. Comparisons with clinical data show that tocilizumab PK after SC administration behind the ear translates best to humans, considering both bioavailability and rate of absorption. Whether this translation from minipigs to humans is prototypic for other mAb remains to be confirmed.

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Acknowledgments

The authors thank Ulrik Westrup, Westrup Vet. Consulting, for ultrasound evaluations in this study.

Funding

This work was funded by F. Hoffmann-La Roche Ltd.

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Author notes

  1. Chris Muenzer

    Present address: Device Development & Commercialization, Technical Research & Development, Novartis AG, 4056, Basel, Switzerland

Authors and Affiliations

  1. Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070, Basel, Switzerland

    Wolfgang F. Richter, Hans-Peter Grimm, Marie-Hélène Gouy, Caroline Kreuzer & Dragomir Draganov

  2. Charles River Laboratories Copenhagen A/S, Hestehavevej 36A, Ejby, 4623, Lille Skensved, Denmark

    Susi Søgaard

  3. Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Munich, Roche Diagnostics GmbH, 82377, Penzberg, Germany

    Uwe Wessels

  4. Device Development, Pharmaceutical Technical Development Europe, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070, Basel, Switzerland

    Chris Muenzer & Tonio Hoche

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  1. Wolfgang F. Richter
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Correspondence to Wolfgang F. Richter.

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The study was performed in accordance with the license to perform experimental animal studies given by the Animal Experiments Inspectorate, Danish Veterinary and Food Administration, Ministry of Environment and Food of Denmark.

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Richter, W.F., Grimm, HP., Gouy, MH. et al. Subcutaneous Site-of-Absorption Study with the Monoclonal Antibody Tocilizumab in Minipigs: Administration Behind Ear Translates Best to Humans. AAPS J 22, 63 (2020). https://doi.org/10.1208/s12248-020-00446-z

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