Pharmacokinetics, tissue distribution and excretion of 40kDa PEG and PEGylated rFVIII (N8-GP) in rats

The biologic fate of the [3H]PEG-moiety incorporated into N8-GP was evaluated based on single i.v. bolus doses to rats. Furthermore, the 40kDa [3H]PEG-moiety was given separately to rats by single i.v. bolus doses, to investigate if the pharmacokinetics were dose-dependent. For both compounds, plasm...

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Bibliographic Details
Published in:European journal of pharmaceutical sciences 2016-05, Vol.87, p.58-68
Main Authors: Bjørnsdottir, Inga, Sternebring, Ola, Kappers, Wendela A., Selvig, Helle, Kornø, Hanne T., Kristensen, Jesper B., Bagger, Morten A.
Format: Article
Language:English
Subjects:
Animals
Distribution
Dose-Response Relationship, Drug
Excretion
Factor VIII - administration & dosage
Factor VIII - pharmacokinetics
Half-Life
Male
N8-GP
PEGylated rFVIII
Pharmacokinetics
Polyethylene Glycols - administration & dosage
Polyethylene Glycols - pharmacokinetics
Radioactive Tracers
Rats
Tissue Distribution
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Summary:The biologic fate of the [3H]PEG-moiety incorporated into N8-GP was evaluated based on single i.v. bolus doses to rats. Furthermore, the 40kDa [3H]PEG-moiety was given separately to rats by single i.v. bolus doses, to investigate if the pharmacokinetics were dose-dependent. For both compounds, plasma pharmacokinetics, distribution and excretion pathways were investigated, based on total radioactivity measurements ([3H]N8-GP: 0.17–4.1mg/kg;~1300–30,000U/kg, PEG load of ~0.03–0.7mg/kg); ([3H]PEG: 0.6, 1, 12, 100 and 200mg/kg). The plasma concentration of the intact N8-GP conjugate was also measured by ELISA. After single i.v. administration to rats, both [3H]N8-GP and [3H]PEG were shown to be widely distributed, mainly in highly vascularized tissues, with the lowest levels of radioactivity found in the CNS. Though a slow elimination of radioactivity was observed over the 12-week study period, approximately half of the radioactive dose of either compound was removed from the body 1week post-dose. The radioactivity was eliminated mainly via the kidney into urine but also via the liver into feces, with a larger fraction found in the feces for [3H]N8-GP. Elimination of the 40kDa PEG-moiety was shown to be dose-dependent with faster elimination at lower dose levels. The clinical dose of N8-GP provides a substantially lower PEG exposure (50–75U/kg; PEG load of
ISSN:0928-0987
1879-0720
DOI:10.1016/j.ejps.2015.10.020