title: PEGylated proteins: evaluation of their safety in the absence of definitive metabolism studies.
abstract: During the development of any PEGylated protein or peptide, toxicology in relevant species will be conducted prior to human exposure. Normally, comprehensive metabolism data accompany the toxicity studies for a small molecule. We have examined whether such studies would be relevant in the safety assessment of PEGylated material. Literature data indicate that the polyethylene glycol (PEG) associated with a biological molecule should provide no extra concern because the exposure-toxicity relationship of PEG in animals and humans has been thoroughly investigated and metabolism/excretion of PEG is well understood. Based on the comparisons of PEG exposure from PEGylated biological products and the exposure of PEG associated with toxicity in humans, the therapeutic index is large (approximately 600-fold or greater). Therefore, assuming that toxicological evaluation of a biological molecule of interest is complete and satisfactory therapeutic windows are achieved, the data contained in this review indicate that the PEG associated with a protein or other biological molecule does not represent an additional unquantified risk to humans.
authors.affiliation: Pfizer Global Research and Development, Pharmacokinetic, Dynamics and Metabolism (IPC 351), Sandwich, Kent, CT13 9NJ, UK. rob.webster@pfizer.com
authors.forename: Rob
authors.initials: R
authors.lastname: Webster
authors.forename: Eric
authors.initials: E
authors.lastname: Didier
authors.forename: Philip
authors.initials: P
authors.lastname: Harris
authors.forename: Ned
authors.initials: N
authors.lastname: Siegel
authors.forename: Jeanne
authors.initials: J
authors.lastname: Stadler
authors.forename: Lorraine
authors.initials: L
authors.lastname: Tilbury
authors.forename: Dennis
authors.initials: D
authors.lastname: Smith
mesh_terms: D000818:Animals; D006801:Humans; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D011506:Proteins / Q000737:chemistry / Q000633:toxicity*
chemical_list: D011506:Proteins; D011092:Polyethylene Glycols