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

Autor: Bjørnsdottir I; Development DMPK and Isotope Chemistry, Novo Nordisk A/S, Novo Nordisk Park, Måløv, Denmark. Electronic address: Inbj@novonordisk.com., Sternebring O; Development DMPK and Isotope Chemistry, Novo Nordisk A/S, Novo Nordisk Park, Måløv, Denmark., Kappers WA; Development DMPK and Isotope Chemistry, Novo Nordisk A/S, Novo Nordisk Park, Måløv, Denmark., Selvig H; Development DMPK and Isotope Chemistry, Novo Nordisk A/S, Novo Nordisk Park, Måløv, Denmark., Kornø HT; Development DMPK and Isotope Chemistry, Novo Nordisk A/S, Novo Nordisk Park, Måløv, Denmark., Kristensen JB; Development DMPK and Isotope Chemistry, Novo Nordisk A/S, Novo Nordisk Park, Måløv, Denmark., Bagger MA; Development DMPK and Isotope Chemistry, Novo Nordisk A/S, Novo Nordisk Park, Måløv, Denmark.
Jazyk: angličtina
Zdroj: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2016 May 25; Vol. 87, pp. 58-68. Date of Electronic Publication: 2015 Oct 27.
DOI: 10.1016/j.ejps.2015.10.020
Abstrakt: The biologic fate of the [(3)H]PEG-moiety incorporated into N8-GP was evaluated based on single i.v. bolus doses to rats. Furthermore, the 40kDa [(3)H]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 ([(3)H]N8-GP: 0.17-4.1mg/kg;~1300-30,000U/kg, PEG load of ~0.03-0.7mg/kg); ([(3)H]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 [(3)H]N8-GP and [(3)H]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 [(3)H]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 <0.002mg/kg) when compared to the PEG doses investigated in this paper (0.03-200mg/kg). This may imply an even faster clearance of the PEG-moiety after N8-GP administration of clinically relevant doses.
(Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: