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MAbs. 2012 Mar-Apr;4(2):243-55. doi: 10.4161/mabs.4.2.19387. Epub 2012 Mar 1.

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

Author information

1
Research and Early Development; Genentech; South San Francisco, CA USA; These authors contributed equally to this work.
2
Drug Metabolism and Pharmacokinetics; Pharma Research and Early Development; Hoffmann-La Roche Inc.; Nutley, NJ USA.
3
Pharma Research and Early Development; F. Hoffmann-La Roche Ltd.; Basel, Switzerland.
4
Research and Early Development; Genentech; South San Francisco, CA USA.
5
Drug Delivery, Pharma Technical Development; Genentech; South San Francisco, CA USA.

Abstract

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.

KEYWORDS:

animal model; mAb IgG; minipig; neonatal Fc receptor (FcRn); pharmacokinetics; subcutaneous bioavailability

PMID:
22453096
PMCID:
PMC3361660
DOI:
10.4161/mabs.4.2.19387
[Indexed for MEDLINE]
Free PMC Article

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