Overview of recent topics in clinical pharmacology of anticancer agents.

The rationale for studying the clinical pharmacology of antineoplastic agents is that the information obtained will result in enhanced drug development and enhanced or improved clinical use. A great deal of effort has been expended in studying the pharmacokinetics and pharmacodynamics of investigational and noninvestigational antineoplastic agents. More recently, a deeper appreciation has developed regarding the importance of the metabolism of antineoplastic agents and the potential role of metabolites in their activity or toxicity, as well as the potential for drug-drug interactions. Investigators studying the clinical pharmacology of antineoplastic agents face an increasingly challenging task as new agents continue to be developed. Some of these challenges arise from the enhanced potency of new agents, resulting in increased difficulty in measuring such agents in biological matrices. Furthermore, as agents have been developed to affect specific biological targets, the necessity of assessing pharmacodynamics at the biochemical or molecular level has become increasingly important. In addition, development of agents with cytostatic, as opposed to cytotoxic, properties poses a further challenge to assessment of pharmacologic effect. In addressing these challenges, a great deal of effort has been expended to develop increasingly sensitive analytical chemical techniques, in evaluating alternative biological matrices, such as saliva, in which to monitor drug concentrations in a less invasive fashion, and in developing limited sampling strategies to assess both the pharmacokinetics and pharmacodynamics of antineoplastic agents. Similarly, a great deal of effort has been expended in providing suitable means for assessing the numerous novel targets for which antineoplastic agents are being developed. These include the assessment of cell cycle kinetics and specific oncoproteins, definition of cell damage such as cleavable complexes, and formation of drug-macromolecular adducts in suitable target cells. Additional effort is being expended to explore nontraditional means of drug delivery. In this regard, the increasing importance of orally administered agents reflects a fundamental change in the approach to antineoplastic drug delivery. Finally, the increased computational power made available by faster personal computers has facilitated a number of innovative modeling techniques involving population modeling, modeling of combination chemotherapy, and assessment of drug-drug interactions.