PHARMACODYNAMIC ASPECTS OF PEPTIDE ADMINISTRATION BIOLOGICAL RESPONSEMODIFIERS

Cytokines, growth factors and other recombinant proteins have been one of the most rapidly growing areas of pharmaceuticals. Further, the de velopment of these bio-engineered drugs is occurring at an astonishing pace with rapid preclinical and clinical development and licensing by regulatory agencies. In addition, the availability of the gene sequen ces and rational drug design technologies have resulted in a rapid dev elopment of engineered genes, proteins and peptidomimetics. In contras t to traditional pharmacophores, which are developed based on the iden tification of the maximum tolerated dose (MTD), most recombinant prote ins have abnormal biodistributions, and pharmacodynamic and pharmacoki netic attributes. Within this chapter, representative cytokines includ ing interferon-alpha (IFN-alpha), IFN-gamma and interleukin-2 are used to discuss the pharmacodynamic aspects of protein/peptide administrat ion that are important in the development of these drugs. This include s the conceptual need for chronic immunoaugmentation for optimal thera peutic activity; the need to consider the pharmacokinetics of administ ration to optimize drug delivery and the nonlinear dose response relat ionship, which can result in a bell shaped dose response. Furthermore, these therapeutics have maximal potential in an adjuvant protocol and their development in combination with high-dose chemotherapy and stem cell rescue is discussed. The strategies for combination chemotherapy and immunotherapy, while holding great promise, require close attenti on to the pharmacodynamics of protein administration in order to impac t on failure free and overall survival. (C) 1998 Published by Elsevier Science B.V. All rights reserved.