Minipig as a potential translatable model for monoclonal antibody pharmacokinetics after intravenous and subcutaneous administration.

Autor:	Zheng Y; Research and Early Development; Genentech; South San Francisco, CA USA; These authors contributed equally to this work., Tesar DB; Research and Early Development; Genentech; South San Francisco, CA USA; These authors contributed equally to this work., Benincosa L; Drug Metabolism and Pharmacokinetics; Pharma Research and Early Development; Hoffmann-La Roche Inc.; Nutley, NJ USA., Birnböck H; Pharma Research and Early Development; F. Hoffmann-La Roche Ltd.; Basel, Switzerland., Boswell CA; Research and Early Development; Genentech; South San Francisco, CA USA., Bumbaca D; Research and Early Development; Genentech; South San Francisco, CA USA., Cowan KJ; Research and Early Development; Genentech; South San Francisco, CA USA., Danilenko DM; Research and Early Development; Genentech; South San Francisco, CA USA., Daugherty AL; Drug Delivery, Pharma Technical Development; Genentech; South San Francisco, CA USA., Fielder PJ; Research and Early Development; Genentech; South San Francisco, CA USA., Grimm HP; Pharma Research and Early Development; F. Hoffmann-La Roche Ltd.; Basel, Switzerland., Joshi A; Research and Early Development; Genentech; South San Francisco, CA USA., Justies N; Pharma Research and Early Development; F. Hoffmann-La Roche Ltd.; Basel, Switzerland., Kolaitis G; Drug Metabolism and Pharmacokinetics; Pharma Research and Early Development; Hoffmann-La Roche Inc.; Nutley, NJ USA., Lewin-Koh N; Research and Early Development; Genentech; South San Francisco, CA USA., Li J; Research and Early Development; Genentech; South San Francisco, CA USA., McVay S; Research and Early Development; Genentech; South San Francisco, CA USA., O'Mahony J; Research and Early Development; Genentech; South San Francisco, CA USA., Otteneder M; Pharma Research and Early Development; F. Hoffmann-La Roche Ltd.; Basel, Switzerland., Pantze M; Pharma Research and Early Development; F. Hoffmann-La Roche Ltd.; Basel, Switzerland., Putnam WS; Research and Early Development; Genentech; South San Francisco, CA USA., Qiu ZJ; Research and Early Development; Genentech; South San Francisco, CA USA., Ruppel J; Research and Early Development; Genentech; South San Francisco, CA USA., Singer T; Pharma Research and Early Development; F. Hoffmann-La Roche Ltd.; Basel, Switzerland., Stauch O; Pharma Research and Early Development; F. Hoffmann-La Roche Ltd.; Basel, Switzerland., Theil FP; Research and Early Development; Genentech; South San Francisco, CA USA., Visich J; Research and Early Development; Genentech; South San Francisco, CA USA., Yang J; Research and Early Development; Genentech; South San Francisco, CA USA., Ying Y; Research and Early Development; Genentech; South San Francisco, CA USA., Khawli LA; Research and Early Development; Genentech; South San Francisco, CA USA., Richter WF; Pharma Research and Early Development; F. Hoffmann-La Roche Ltd.; Basel, Switzerland.
Jazyk:	angličtina
Zdroj:	MAbs [MAbs] 2012 Mar-Apr; Vol. 4 (2), pp. 243-55. Date of Electronic Publication: 2012 Mar 01.
DOI:	10.4161/mabs.4.2.19387
Abstrakt:	Subcutaneous (SC) delivery is a common route of administration for therapeutic monoclonal antibodies (mAbs) with pharmacokinetic (PK)/pharmacodynamic (PD) properties requiring long-term or frequent drug administration. An ideal in vivo preclinical model for predicting human PK following SC administration may be one in which the skin and overall physiological characteristics are similar to that of humans. In this study, the PK properties of a series of therapeutic mAbs following intravenous (IV) and SC administration in Göttingen minipigs were compared with data obtained previously from humans. The present studies demonstrated: (1) minipig is predictive of human linear clearance; (2) the SC bioavailabilities in minipigs are weakly correlated with those in human; (3) minipig mAb SC absorption rates are generally higher than those in human and (4) the SC bioavailability appears to correlate with systemic clearance in minipigs. Given the important role of the neonatal Fc-receptor (FcRn) in the PK of mAbs, the in vitro binding affinities of these IgGs against porcine, human and cynomolgus monkey FcRn were tested. The result showed comparable FcRn binding affinities across species. Further, mAbs with higher isoelectric point tended to have faster systemic clearance and lower SC bioavailability in both minipig and human. Taken together, these data lend increased support for the use of the minipig as an alternative predictive model for human IV and SC PK of mAbs.
Databáze:	MEDLINE
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