Dosage regimen design: pharmacodynamic considerations

Pharmacokinetic methodology to define the time course of drug in an accessible biologic fluid is now well established as are models that relate concentration to effect. When steady-state conditions are not readily available to define a dose- or concentration-effect relationship, non-steady-state pharmacokinetic/pharmacodynamic models can be applied. Despite these methodologic advances, many aspects of clinical drug development and therapy do not readily lend themselves to pharmacokinetic/pharmacodynamic scrutiny. Barriers to this scrutiny include: drug assay problems or lack of an accessible biologic fluid that can be sampled to measure drug concentration; lack of a immediate pharmacologic effect in the clinic that can be related to concentration; and lack of a relationship between an immediate measurable pharmacologic effect and long-term clinical benefit. In the evaluation and application of any drug, the following questions are useful: 1) what is the pharmacologic effect of interest? 2) is it a positive (benefit) or negative (risk) effect? 3) are there more than one positive or negative effects of interest? 4) how is the effect measured and can the measurement be applied reasonably in a clinical setting? 5) is the effect immediate (for example, blood pressure reduction) or long-term (for example, prevention of stroke with an antihypertensive)? 6) can the effect be usefully related to a concentration to guide dosimetry? and 6) if a concentration/effect relationship is likely, can it be defined at steady state or must non-steady-state pharmacokinetic/pharmacodynamic models be constructed?(ABSTRACT TRUNCATED AT 250 WORDS)