PMID- 25644368
OWN - NLM
STAT- MEDLINE
DCOM- 20160422
LR  - 20181202
IS  - 1543-8392 (Electronic)
IS  - 1543-8384 (Linking)
VI  - 12
IP  - 3
DP  - 2015 Mar 2
TI  - PEGylation does not significantly change the initial intravenous or subcutaneous 
      pharmacokinetics or lymphatic exposure of trastuzumab in rats but increases 
      plasma clearance after subcutaneous administration.
PG  - 794-809
LID - 10.1021/mp5006189 [doi]
AB  - The lymphatic system plays a major role in the metastatic dissemination of cancer 
      and has an integral role in immunity. PEGylation enhances drainage and lymphatic 
      uptake following subcutaneous (sc) administration of proteins and protein-like 
      polymers, but the impact of PEGylation of very large proteins (such as 
      antibodies) on subcutaneous and lymphatic pharmacokinetics is unknown. This study 
      therefore aimed to evaluate the impact of PEGylation on the sc absorption and 
      lymphatic disposition of the anti-HER2 antibody trastuzumab in rats. 
      PEG-trastuzumab was generated via the conjugation of a single 40 kDa PEG-NHS 
      ester to trastuzumab. PEG-trastuzumab showed a 5-fold reduction in HER2 binding 
      affinity, however the in vitro growth inhibitory effects were preserved as a 
      result of changes in cellular trafficking when compared to native trastuzumab. 
      The lymphatic pharmacokinetics of PEG-trastuzumab was evaluated in thoracic lymph 
      duct cannulated rats after iv and sc administration and compared to the 
      pharmacokinetics of native trastuzumab. The iv pharmacokinetics and lymphatic 
      exposure of PEG-trastuzumab was similar when compared to trastuzumab. After sc 
      administration, initial plasma pharmacokinetics and lymphatic exposure were also 
      similar between PEG-trastuzumab and trastuzumab, but the absolute bioavailability 
      of PEG-trastuzumab was 100% when compared to 86.1% bioavailability for 
      trastuzumab. In contrast to trastuzumab, PEG-trastuzumab showed accelerated 
      plasma clearance beginning approximately 7 days after sc, but not iv, 
      administration, presumably as a result of the generation of anti-PEG IgM. This 
      work suggests that PEGylation does not significantly alter the lymphatic 
      disposition of very large proteins, and further suggests that it is unlikely to 
      benefit therapy with monoclonal antibodies.
FAU - Chan, Linda J
AU  - Chan LJ
AD  - Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical 
      Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, 
      Australia.
FAU - Bulitta, Jurgen B
AU  - Bulitta JB
FAU - Ascher, David B
AU  - Ascher DB
FAU - Haynes, John M
AU  - Haynes JM
FAU - McLeod, Victoria M
AU  - McLeod VM
FAU - Porter, Christopher J H
AU  - Porter CJ
FAU - Williams, Charlotte C
AU  - Williams CC
FAU - Kaminskas, Lisa M
AU  - Kaminskas LM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150218
PL  - United States
TA  - Mol Pharm
JT  - Molecular pharmaceutics
JID - 101197791
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Immunoglobulin M)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - P188ANX8CK (Trastuzumab)
SB  - IM
MH  - Administration, Intravenous
MH  - Animals
MH  - Antineoplastic Agents/*administration & dosage/chemistry/*pharmacokinetics
MH  - Biopharmaceutics
MH  - Capillary Permeability
MH  - Cell Line, Tumor
MH  - Human Umbilical Vein Endothelial Cells
MH  - Humans
MH  - Immunoglobulin M/biosynthesis/blood
MH  - Injections, Subcutaneous
MH  - Lymph/metabolism
MH  - Lymphatic System/metabolism
MH  - Male
MH  - Metabolic Clearance Rate
MH  - Models, Biological
MH  - Polyethylene Glycols/adverse effects/chemistry
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Trastuzumab/*administration & dosage/chemistry/*metabolism
OTO - NOTNLM
OT  - HER2
OT  - PEGylation
OT  - S-ADAPT
OT  - lymphatic
OT  - monoclonal antibody
OT  - pharmacokinetics
OT  - population modeling
OT  - trastuzumab
EDAT- 2015/02/04 06:00
MHDA- 2016/04/23 06:00
CRDT- 2015/02/04 06:00
PHST- 2015/02/04 06:00 [entrez]
PHST- 2015/02/04 06:00 [pubmed]
PHST- 2016/04/23 06:00 [medline]
AID - 10.1021/mp5006189 [doi]
PST - ppublish
SO  - Mol Pharm. 2015 Mar 2;12(3):794-809. doi: 10.1021/mp5006189. Epub 2015 Feb 18.