Pharmacodynamic evaluation of a PEGylated analogue of human growth hormone releasing factor in rats and pigs.
The aim of this study was to assess the in vivo efficacy of monoPEGylated GRF(1-29)NH(2) having one PEG(5000) chains attached to either lysine 12 or 21 as compared to the GRF(1-29)NH(2) in rats and pigs. This analogue termed GRF-1PEG(5000) was tested after a single intravenous administration in rats and after a single intravenous or subcutaneous injection in pigs. After 1 h administration, GH concentrations returned to values close to controls in the group of rats injected with GRF(1-29)NH(2). In animals injected with the same dose of GRF-1PEG(5000), the AUC values corresponding to the whole period 0.5-48 h and particularly to the 0.5-8 h period were higher than in the placebo or in the GRF(1-29)NH(2) groups. Interestingly, two additional peaks were observed at about 6 and 8 h following administration. An increase in the response of the endogenous GH peaks was also observed in pigs administered GRF-1PEG(5000) by intravenous route. When GRF-1PEG(5000) was administered subcutaneously to pigs, a significant increase, as compared to placebo and GRF(1-29)NH(2,) in both GH and IGF-I levels was observed. This new analogue might find therapeutic application in paediatric growth hormone deficiency or in aging.
D'Antonio
M
M
Industria Farmaceutica Serono SpA, Drug Delivery Systems, Via Ribes 5, I-10010 Colleretto Giacosa, Turin, Italy. mauro.d'antonio@serono.com
Louveau
I
I
Esposito
P
P
Bertolino
M
M
Canali
S
S
D000818:Animals; D013006:Growth Hormone / Q000097:blood / Q000378:metabolism; D013007:Growth Hormone-Releasing Hormone / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000378:metabolism; D008297:Male; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017337:Sermorelin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013552:Swine
C494224:GRF-1PEG500; D011092:Polyethylene Glycols; D007334:Insulin-Like Growth Factor I; D017337:Sermorelin; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone