DETERMINATION OF TIME-DEPENDENT EFFECT PR OFILE OF DRUGS

Therapeutic benefit that can be induced by a pharmaceutical compound p artly relies upon the profile of its biological action. Evaluation of the drug-induced effect profile in a given pathological condition begi ns with the determination of the relevant biological effect related to the therapeutic benefit, which is not always obvious. Evaluation itse lf is based on dose-effect relationships as a function of time. During chronic treatment, such a kinetic profile oscillates between peak and trough levels. Relationships that can be established between time-dep endent effect profile and pharmacokinetic data lead to PK-PD mathemati cal model, whose main objectives are simulation, prediction of effect and ultimately dose optimisation. The therapeutic implications of the time-dependent effect profile are well illustrated in the cases of ant ibiotics, diuretics such as furosemide and anti-hypertensive drugs. Du ring drug development, PK-PD approaches can be used in the initial cli nical and even pre-clinical phases and can lead to a better definition of effective dose ranges, optimisation of large scale clinical trials or identification of high risk patients. This may favour a reduction of costs and duration of development. Validation of such an approach i s easier in well known therapeutic domains but can be more difficult w ith innovative drugs. The implications of PK-PD approaches can however , be, limited when the relevant biological or clinical parameter canno t be assessed, when the cascade of events leading to pharmacological a nd therapeutic effects is complex or finally when such PK-PD models re quire a long time to be established during the early phase of drug dev elopment.