Polymer conjugates. Pharmacokinetic considerations for design and development.

Soluble polymer conjugates have only recently been introduced into clinical practice. They can be subdivided into 2 main categories: polymer-protein conjugates, so far the most widely studied; and polymer-drug conjugates, particularly those containing conventional antitumour agents, that are still at an early stage of development. Polymer conjugation can be used to alter the biodistribution, elimination and rate of metabolism of covalently bound drugs. In the case of protein adducts, polymer conjugation prolongs the protein plasma elimination half-life (5- to 500-fold increases in elimination half-life have been reported), reduces proteolytic degradation and has the added benefit of reducing immunogenicity. Cellular uptake of low molecular weight drugs convalently bound to polymeric carriers is restricted to the endocytic route. Thus, the organ and subcellular distribution of the drug can be modified. Cellular uptake has been used to facilitate drug targeting and decreased toxicity. In this review, the theoretical rationale for polymer conjugation is described, as is the limited clinical pharmacokinetic experience with polymer conjugates. As an alteration of the pharmacokinetic profile of a drug was one of the underlying arguments for creation of polymeric conjugates, more clinical pharmacokinetic studies are urgently needed to permit the validation of appropriate pharmacokinetic models that can be used in the future to assist in the optimisation of clinical protocols, and improved conjugate design.