PHARMACOKINETICS AND PHARMACODYNAMICS OF RECOMBINANT PROTEINS AND PEPTIDES

Recombinant derived proteins and peptides are becoming increasingly important as therapeutic agents. The successful development of recombinant proteins depends on the proper characterization of their pharmacokinetics and an understanding of the relationship between drug exposure or dose and the pharmacological response. Although many traditional pharmacokinetic principles can be applied to recombinant proteins and peptides, biotechnologically derived agents also pose some new challenges. Pharmacokinetic characterization of proteins is often complicated due to the absence of a specific assay, difficulties in identifying metabolites, endogenous circulating concentrations, and the presence of binding proteins. The ubiquitous distribution of proteases leads to significant degradation and relatively short circulation times in the body. The protein concentration in the circulation may not correlate with the pharmacological effect and it may be difficult to identify or sample the biophase. Numerous methods have been explored for increasing the residence time of proteins and enhancing the pharmacological effect. Some of the techniques that have been employed include site-specific mutagenesis, polymer-modifications and fusion with immunoglobulins, targeting through the use of liposomes or conjugation to toxins, radionuclides and other proteins. An increase in the residence time does not always lead to an enhanced therapeutic effect and these methods have resulted in variable degrees of success. The intricate relationship between pharmacokinetic and pharmacodynamic properties of recombinant proteins is discussed. Examples are presented to illustrate the diversity of approaches that have been employed to improve the therapeutic efficacy of recombinant proteins.