title: Minipig as a potential translatable model for monoclonal antibody pharmacokinetics after intravenous and subcutaneous administration.
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.
authors.affiliation: Research and Early Development; Genentech; South San Francisco, CA USA; These authors contributed equally to this work.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Research and Early Development; Genentech; South San Francisco, CA USA; These authors contributed equally to this work.
authors.forename: Devin B
authors.initials: DB
authors.lastname: Tesar
authors.affiliation: Drug Metabolism and Pharmacokinetics; Pharma Research and Early Development; Hoffmann-La Roche Inc.; Nutley, NJ USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Benincosa
authors.affiliation: Pharma Research and Early Development; F. Hoffmann-La Roche Ltd.; Basel, Switzerland.
authors.forename: Herbert
authors.initials: H
authors.lastname: Birnböck
authors.affiliation: Research and Early Development; Genentech; South San Francisco, CA USA.
authors.forename: C Andrew
authors.initials: CA
authors.lastname: Boswell
authors.affiliation: Research and Early Development; Genentech; South San Francisco, CA USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bumbaca
authors.affiliation: Research and Early Development; Genentech; South San Francisco, CA USA.
authors.forename: Kyra J
authors.initials: KJ
authors.lastname: Cowan
authors.affiliation: Research and Early Development; Genentech; South San Francisco, CA USA.
authors.forename: Dimitry M
authors.initials: DM
authors.lastname: Danilenko
authors.affiliation: Drug Delivery, Pharma Technical Development; Genentech; South San Francisco, CA USA.
authors.forename: Ann L
authors.initials: AL
authors.lastname: Daugherty
authors.affiliation: Research and Early Development; Genentech; South San Francisco, CA USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fielder
authors.affiliation: Pharma Research and Early Development; F. Hoffmann-La Roche Ltd.; Basel, Switzerland.
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Grimm
authors.affiliation: Research and Early Development; Genentech; South San Francisco, CA USA.
authors.forename: Amita
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Pharma Research and Early Development; F. Hoffmann-La Roche Ltd.; Basel, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Justies
authors.affiliation: Drug Metabolism and Pharmacokinetics; Pharma Research and Early Development; Hoffmann-La Roche Inc.; Nutley, NJ USA.
authors.forename: Gerry
authors.initials: G
authors.lastname: Kolaitis
authors.affiliation: Research and Early Development; Genentech; South San Francisco, CA USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Lewin-Koh
authors.affiliation: Research and Early Development; Genentech; South San Francisco, CA USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Research and Early Development; Genentech; South San Francisco, CA USA.
authors.forename: Sami
authors.initials: S
authors.lastname: McVay
authors.affiliation: Research and Early Development; Genentech; South San Francisco, CA USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: O'Mahony
authors.affiliation: Pharma Research and Early Development; F. Hoffmann-La Roche Ltd.; Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Otteneder
authors.affiliation: Pharma Research and Early Development; F. Hoffmann-La Roche Ltd.; Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Pantze
authors.affiliation: Research and Early Development; Genentech; South San Francisco, CA USA.
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Putnam
authors.affiliation: Research and Early Development; Genentech; South San Francisco, CA USA.
authors.forename: Zhihua J
authors.initials: ZJ
authors.lastname: Qiu
authors.affiliation: Research and Early Development; Genentech; South San Francisco, CA USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Ruppel
authors.affiliation: Pharma Research and Early Development; F. Hoffmann-La Roche Ltd.; Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Singer
authors.affiliation: Pharma Research and Early Development; F. Hoffmann-La Roche Ltd.; Basel, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Stauch
authors.affiliation: Research and Early Development; Genentech; South San Francisco, CA USA.
authors.forename: Frank-Peter
authors.initials: FP
authors.lastname: Theil
authors.affiliation: Research and Early Development; Genentech; South San Francisco, CA USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Visich
authors.affiliation: Research and Early Development; Genentech; South San Francisco, CA USA.
authors.forename: Jihong
authors.initials: J
authors.lastname: Yang
authors.affiliation: Research and Early Development; Genentech; South San Francisco, CA USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ying
authors.affiliation: Research and Early Development; Genentech; South San Francisco, CA USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Khawli
authors.affiliation: Pharma Research and Early Development; F. Hoffmann-La Roche Ltd.; Basel, Switzerland.
authors.forename: Wolfgang F
authors.initials: WF
authors.lastname: Richter
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D018448:Models, Immunological; D013552:Swine; D013556:Swine, Miniature
chemical_list: D000911:Antibodies, Monoclonal