Current concepts in pharmacokinetics and their implications for clinical medicine.

The history of medicine provides ample evidence of the physicians' struggle with the subject of appropriate drug dosing. Recent studies indicate that drug-related mortality due to inadequate dosing principles still is a leading cause of death, only surpassed by cardiovascular diseases, cancer and stroke. In an effort to rationalize drug therapy, pharmacokinetic (PK) principles were introduced in medical practice in the early 1970s, mainly in the field of therapeutic drug monitoring (TDM). This measure was shown to reduce mortality. Several limitations in traditional PK, however, have led to the belief among many physicians that clinical PK is an unnecessary assignment of limited clinical relevance. Despite the perceived limitations of traditional PK research, remarkable developments have taken place in recent years and have made clinical PK a "physiological-mechanism based endeavor" with important implications for clinical medicine. Notably, the introduction of (1) PK-PD (pharmacokinetic-pharmacodynamic) modeling (2) target site PK (3) population PK and (4) pharmacogenomics has permitted better integration of PK principles into clinical drug therapy. The aim of the present article is to provide an overview of these developments and to discuss their impact on our understanding of clinical drug therapy.