Pharmacokinetic/pharmacodynamic (PK/PD) differentiation of native and PEGylated recombinant human growth hormone (rhGH and PEG-rhGH) in the rat model of osteoarthritis.
Osteoarthritis (OA) is a degenerative joint disease that has no FDA-approved treatment. The current standard of care does not address the regeneration of the damaged cartilage. Human growth hormone (hGH) is part of the insulin-like growth factor (IGF)-1 axis. There has been preclinical data that suggest its potential regenerative property in the joint. However, unformulated recombinant hGH (rhGH) is short-lived in the joint, and does not provide a desirable pharmacokinetic (PK) profile to support a clinical treatment paradigm. Polyethylene glycol (PEG)ylation is a potential method to extend the half-life of rhGH in the joint. The purpose of this study was to delineate the PK/PD profile of PEG-rhGH in the knee joint in a rat preclinical model of OA. After intra-articular (IA) injection of 100 microg into a rat knee joint that underwent medial meniscectomy, PEG-rhGH exhibits 2-fold longer half-lives in joint than native hGH. However, PEG-rhGH has a much longer systemic exposure. IA injections of PEG-rhGH also resulted in higher levels of IGF-1 in the joint and serum when compared with native rhGH. In order to develop PEG-rhGH as an IA therapeutic treatment for OA, careful dose selection is necessary to avoid systemic effects while retaining its anabolic efficacy in the joint.
Pfizer Global Research and Development, St. Louis Laboratories, St. Louis, MO 63017, USA. olga.v.nemirovskiy@pfizer.com
Olga
O
Nemirovskiy
Yi J
YJ
Zheng
David
D
Tung
Brian
B
Korniski
Steve
S
Settle
Adam
A
Skepner
Matthew
M
Yates
Poonam
P
Aggarwal
Teresa
T
Sunyer
Dean J
DJ
Aguiar
D000818:Animals; D004195:Disease Models, Animal; D006207:Half-Life; D019382:Human Growth Hormone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D008297:Male; D010003:Osteoarthritis / Q000188:drug therapy / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000493:pharmacokinetics*
D011994:Recombinant Proteins; D019382:Human Growth Hormone; D011092:Polyethylene Glycols