PMID- 29355621
OWN - NLM
STAT- MEDLINE
DCOM- 20190318
LR  - 20190318
IS  - 1873-4995 (Electronic)
IS  - 0168-3659 (Linking)
VI  - 273
DP  - 2018 Mar 10
TI  - In vitro model for predicting bioavailability of subcutaneously injected 
      monoclonal antibodies.
PG  - 13-20
LID - S0168-3659(18)30025-7 [pii]
LID - 10.1016/j.jconrel.2018.01.015 [doi]
AB  - Monoclonal antibodies (mAbs), which are now more frequently administered by 
      subcutaneous (SC) injection rather than intravenously, have become a tremendously 
      successful drug format across a wide range of therapeutic areas. Preclinical 
      evaluations of mAbs to be administered by SC injection are typically performed in 
      species such as mice, rats, minipigs, and cynomolgus monkeys to obtain critical 
      information regarding formulation performance and prediction of PK/PD outcomes 
      needed to select clinical doses for first-in-human studies. Despite extensive 
      efforts, no preclinical model has been identified to date that accurately 
      predicts clinical outcomes for these SC injections. We have addressed this 
      deficiency with a novel in vitro instrument, termed Scissor, to model events 
      occurring at the SC injection site and now further validated this approach using 
      a set of eight mAbs for which clinical PK/PD outcomes have been obtained. 
      Diffusion of these mAbs from the Scissor system injection cartridge into a large 
      volume physiological buffer, used to emulate mAb movement from the SC injection 
      site into the systemic circulation, provided distinct profiles when monitored 
      over a 6h period. Curve-fitting analysis of these profiles using the Hill 
      equation identified parameters that were used, along with physicochemical 
      properties for each mAb, in a partial least squares analysis to define a 
      relationship between molecule and formulation properties with clinical PK 
      outcomes. The results demonstrate that parameters of protein charge at neutral pH 
      and isoelectric point (pI) along with combined formulation properties such as 
      viscosity and mAb concentration can dictate the movement of the mAb from the 
      injection cartridge to infinite sink compartment. Examination of profile 
      characteristics of this movement provided a strong predictive correlation for 
      these eight mAbs. Together, this approach demonstrates the feasibility of this in 
      vitro modelling strategy as a tool to identify drug and formulation properties 
      that can define the performance of SC injected medicines and provide the 
      potential for predicting clinical outcomes that could be useful for formulation 
      selection and a first-in-human clinical dosing strategy.
CI  - Copyright (c) 2018. Published by Elsevier B.V.
FAU - Bown, Hanne Kinnunen
AU  - Bown HK
AD  - School of Medicine, Pharmacy and Health, Division of Pharmacy, Durham University, 
      Stockton-on-Tees TS17 6BH, UK.
FAU - Bonn, Catherine
AU  - Bonn C
AD  - School of Medicine, Pharmacy and Health, Division of Pharmacy, Durham University, 
      Stockton-on-Tees TS17 6BH, UK.
FAU - Yohe, Stefan
AU  - Yohe S
AD  - Drug Delivery, Genentech, Inc., South San Francisco, CA 94080, USA.
FAU - Yadav, Daniela Bumbaca
AU  - Yadav DB
AD  - Preclinical and Translational Pharmacokinetics, Genentech, Inc., South San 
      Francisco, CA 94080, USA.
FAU - Patapoff, Thomas W
AU  - Patapoff TW
AD  - Early Stage Formulation Development, Genentech, Inc., South San Francisco, CA 
      94080, USA.
FAU - Daugherty, Ann
AU  - Daugherty A
AD  - Drug Delivery, Genentech, Inc., South San Francisco, CA 94080, USA.
FAU - Mrsny, Randall J
AU  - Mrsny RJ
AD  - Department of Pharmacy and Pharmacology, University of Bath, Bath, UK. Electronic 
      address: Rjm37@bath.ac.uk.
LA  - eng
GR  - BB/L013770/1/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180206
PL  - Netherlands
TA  - J Control Release
JT  - Journal of controlled release : official journal of the Controlled Release 
      Society
JID - 8607908
RN  - 0 (Antibodies, Monoclonal)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/*administration & dosage/*pharmacokinetics
MH  - Biological Availability
MH  - *Drug Delivery Systems
MH  - Humans
MH  - Injections, Subcutaneous
MH  - Macaca fascicularis
MH  - Mice
MH  - *Models, Biological
MH  - Rats
MH  - Swine
MH  - Swine, Miniature
OTO - NOTNLM
OT  - Formulation design
OT  - Monoclonal antibody
OT  - Subcutaneous injection
OT  - in vitro model
EDAT- 2018/01/23 06:00
MHDA- 2019/03/19 06:00
CRDT- 2018/01/23 06:00
PHST- 2017/09/12 00:00 [received]
PHST- 2018/01/13 00:00 [revised]
PHST- 2018/01/16 00:00 [accepted]
PHST- 2018/01/23 06:00 [pubmed]
PHST- 2019/03/19 06:00 [medline]
PHST- 2018/01/23 06:00 [entrez]
AID - S0168-3659(18)30025-7 [pii]
AID - 10.1016/j.jconrel.2018.01.015 [doi]
PST - ppublish
SO  - J Control Release. 2018 Mar 10;273:13-20. doi: 10.1016/j.jconrel.2018.01.015. 
      Epub 2018 Feb 6.