Pharmacokinetics and Pharmacodynamics of Peptide and Protein Drugs
The rational use of drugs and the design of effective dosage regimens are facilitated by the appreciation of the central paradigm of clinical pharmacology that there is a defined relationship between the administered dose of a drug, the resulting drug concentrations in various body fluids and tissues, and the intensity of pharmacologic effects caused by these concentrations (Meibohm and Derendorf, 1997). This dose–exposure–response relation-ship and thus the dose of a drug required to achieve a certain effect are determined by the drug’s pharmacoki-netic and pharmacodynamic properties (Fig. 1).
Pharmacokinetics describes the time course of the concentration of a drug in a body fluid, preferably plasma or blood, that results from the administration of a certain dosage regimen. It comprises all processes affecting drug absorption, distribution, metabolism, and excretion. Simplified, pharmacokinetics charac-terizes what the body does to the drug. In contrast, pharmacodynamics characterizes the intensity of a drug effect or toxicity resulting from certain drug concentrations in a body fluid, usually at the assumed site of drug action. It can be simplified to what the drugdoes to the body (Fig. 2) (Holford and Sheiner, 1982;Derendorf and Meibohm, 1999).
The understanding of the dose–concentration– effect relationship is crucial to any drug — including peptides and proteins — as it lays the foundation for dosing regimen design and rational clinical application. General pharmacokinetic and pharmacodynamics prin-ciples are to a large extent equally applicable to protein and peptide drugs as they are to traditional small molecule-based therapeutics. Deviations from some of these principles and additional challenges with regard to the characterization of the pharmacokinetics and phar-macodynamics of peptide and protein therapeutics, however, arise from some of their specific properties:
a. Their structural similarity to endogenous struc-tural or functional proteins and nutrients.
b. Their intimate involvement in physiologic pro-cesses on the molecular level, often including regulatory feedback mechanisms.
c. The analytical challenges to identify and quan-tify them in the presence of a myriad of similar molecules.
d. Their large molecular weight and macromolecule character (for proteins).
This chapter will highlight some of the major pharmacokinetic properties and processes relevant for the majority of peptide and protein therapeutics and will provide examples of well-characterized pharmacody-namic relationships for peptide and protein drugs. The clinical pharmacology of monoclonal antibodies, includ-ing special aspects in their pharmacokinetic and phar-macodynamics, will be discussed in further detail. For a more general discussion on pharma-cokinetic and pharmacodynamic principles, the reader is referred to several textbooks and articles that review the topic in extensive detail .