Pharmacokinetics, tissue distribution, excretion, and metabolite profiling of PEGylated rFIX (nonacog beta pegol, N9-GP) in rats

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• 作者：Ola Sternebring ; Jesper Kammersgaard Christensen ; Inga Bjø ; rnsdottir ; ^{Inbj@novonordisk.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ADME ; absorption ; distribution ; metabolism ; and excretion ; AMS ; accelerator mass spectrometry ; AUC ; area under the plasma concentration&ndash ; time curve from zero to infinity ; AUC[0&ndash ; t] ; area under the plasma concentration&ndash ; time curves from zero to time t ; AUCextrap ; extrapolated area under the plasma concentration&ndash ; time curves from the last sampling time point to infinity ; CL ; total plasma clearance ; CLd ; intercompartmental distribution clearance ; C0 ; concentration at time zero
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2016
• 出版时间：20 September 2016
• 年：2016
• 卷：92
• 期：Complete
• 页码：163-172
• 全文大小：808 K

文摘

Nonacog beta pegol (N9-GP) is a novel recombinant factor IX conjugated with a 40-kDa branched polyethylene glycol (PEG) to extend plasma half-life (t_½) compared with native FIX, developed for the treatment of haemophilia B.

This is the first time distribution, metabolism, and excretion data of N9-GP have been presented. ADME studies were performed using single i.v. doses of radiolabelled N9-GP administered to rats, focussing on the biological fate of the 40-kDa PEG. Results indicated that N9-GP-related radioactivity was distributed throughout the body, being most abundant in highly vascularised tissues, and with lowest levels seen in the central nervous system. N9-GP was cleared from plasma within 1 week after dosing, while total radioactivity was eliminated more slowly, in a more pronounced biphasic manner. N9-GP seems to be cleared via receptor-mediated uptake (e.g., in the liver) or via the reticuloendothelial system with subsequent proteolysis. PEG is thereafter either cleared alongside the protein or released back into circulation. Furthermore, N9-GP-related radioactivity was excreted in both faeces and urine as 40 kDa PEG and degradation products. Some PEG-related radioactivity (not in any particular organ) was present in the carcass 12 weeks postdose, consistent with the long terminal elimination t_½ of plasma radioactivity.

As shown here for N9-GP, and previously for other protein-PEG conjugate products, disposition kinetics of conjugates and individual constituents appears to be compound specific. In addition to the size/structure of the PEG and protein moieties, protein-specific clearance pathways may contribute to the disposition of intact conjugate and PEG moiety.