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.
Nemirovskiy
Olga
O
Pfizer Global Research and Development, St. Louis Laboratories, St. Louis, MO 63017, USA. olga.v.nemirovskiy@pfizer.com
Zheng
Yi J
YJ
Tung
David
D
Korniski
Brian
B
Settle
Steve
S
Skepner
Adam
A
Yates
Matthew
M
Aggarwal
Poonam
P
Sunyer
Teresa
T
Aguiar
Dean J
DJ
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