Pharmacodynamic aspects of peptide administration biological response modifiers

Cytokines, growth factors and other recombinant proteins have been one of the most rapidly growing areas of pharmaceuticals. Further, the development 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 sequences and rational drug design technologies have resulted in a rapid development of engineered genes, proteins and peptidomimetics. In contrast to traditional pharmacophores, which are developed based on the identification of the maximum tolerated dose (MTD), most recombinant proteins have abnormal biodistributions, and pharmacodynamic and pharmacokinetic attributes. Within this chapter, representative cytokines including interferon-alpha (IFN-alpha), IFN-gamma and interleukin-2 are used to discuss the pharmacodynamic aspects of protein/peptide administration that are important in the development of these drugs. This includes the conceptual need for chronic immunoaugmentation for optimal therapeutic activity; the need to consider the pharmacokinetics of administration to optimize drug delivery and the nonlinear dose response relationship, 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 attention to the pharmacodynamics of protein administration in order to impact on failure free and overall survival.