Poly (ethylene glycol) Prodrugs: Altered Pharmacokinetics and Pharmacodynamics

Abstract

Pharmacological activity and therapeutic significance are often correlated to the plasma concentration versus profile of the drug. Polymeric prodrugs, as a class, generally achieve areas under the curve (AUCs) of great magnitude, as they slowly release native drug over longer periods of time (Sinko and Kohn, 1993). It has been demonstrated conclusively by Greenwald et al. (1996a,b) that substantial increments to the AUC can be achieved by polyethylene glycol (PEG) conjugation to small molecule drugs if the molecular weight (MW) of the PEG exceeds 20,000 Da. This effect is essentially one of increasing the apparent AUC for the drug itself. It is important that the polymeric species demonstrates good blood and tissue compatibility; for this purpose, a neutral or slightly negative electric charge appears to be optimal since polycationic polymers are readily captured by the first-pass effect, and are known to possess various degrees of toxicity (Maeda, 1992; Nishikawa et al., 1996). The focus of this review will be on the design, applications, and current investigations of polymeric prodrugs with the main emphasis on PEG. The exploitation of PEG prodrugs has been especially effective with anticancer agents, but other drugs in the areas of antibacterials and antifungals have also been successfully modified with PEG to produce prodrugs that demonstrate the desired increased AUCs. It would appear that other types of drugs such as antiviral agents can be similarly modified when a continuous controlled release of drug is desired, but only one report using low molecular weight (LMW) PEG has appeared in the literature (Zacchigna et al., 2002).