PEG and PEG conjugates toxicity: towards an understanding of the toxicity of PEG and its relevance to PEGylated biologicals

Abstract

PEG is used to improve pharmacokinetic properties of biologicals. Concern has been expressed about the toxicological effect and/or fate of the PEG. This paper reviews the available toxicity, metabolism and clearance data of PEG and PEGylated products in order to place such concerns in to appropriate context. The available data demonstrates that PEG itself only shows toxicity at high, parenteral doses and the usual target organ is the kidney as this is the route of excretion for unchanged PEG. A large therapeutic window (approximately 600-fold) exists between the maximum PEG burden from a current biological agent and the doses of PEG associated with human toxicity. Pathological changes which results in no functional deficit, PEG containing vacuoles in cells, have been observed with PEGylated biologicals. There is evidence that these PEG vesicle can resolve with time. In conclusion the doses used clinically for current and many future PEGylated biologicals are low and will result in exposures to PEG significantly lower than that required to elicit PEG toxicity. In all cases the routine regulatory toxicology studies would identify relevant pathology should it occur.