The Role of Pharmacokinetics and Pharmacodynamics in the Development of Therapeutic Proteins

Abstract

Since the degree of preclinical work conducted to address safety issues in animals is usually rate limiting to the initiation of Phase I clinical studies, the preclinical program should be designed to allow rapid entry into the clinic without compromising safety. The establishment of acceptable therapeutic ratios relies on the relationship of doses utilized in toxicology studies and their projected relationship to the clinical dosing regimen. Experience with multiple therapeutic proteins (biomacromolecules) in our laboratory indicates that the pharmacokinetic behavior of many proteins is predictable across species. In selected cases, this information permits extrapolation of preclinical safety and efficacy data to the clinical setting when doses are related on the basis of pharmacokinetic equivalence rather than on a body weight (mg/kg) or body surface area (mg/m²) basis. With a better understanding of this cross species relationship, the confidence in the safety of a therapeutic agent in initial clinical studies is increased. Based on our experience, an approach is presented that maximizes the relevance of the preclinical information gained, minimizes the scope of the initial toxicology studies, and, therefore, minimizes time to initiation of Phase I. This strategy may be useful for selected classes of compounds. Also, several case studies are presented to illustrate how pharmacokinetics was used to bridge the gap between discovery research, preclinical studies, and clinical trials during the development of two therapeutic proteins (rCD4 and rCD4-IgG) for the treatment of Acquired Immunodeficiency Syndrome (AIDS).