Development steps of pharmacokinetics: a perspective on bioanalytical methods and bioequivalence

This paper describes the main development steps of pharmacokinetics that paralleled the development of analytical bioassay methods. From the first stirrings on 1950s, with very sensitive but not specific radiotracing measurements using 14C or 3H labelled drugs, to further developments with more specific methods like gas chromatography, high pressure liquid chromatography, to the last achievement with tandem mass spectrometry, pharmacokinetics has supported all the development procedures of both NDA (New Drug Application) and ANDA (Abridged New Drug Application). The discovery of new therapeutic active molecules is now concentrated in a few very big companies, and requires pharmacokinetic support from the first screening procedures to the last clinical developments. Medium and small pharmaceutical companies largely use pharmacokinetics for various new applications of existing drugs now out of patent, that require only or mainly pharmacokinetic, bioavailability, bioequivalence investigations in compliance with the ANDA procedure. In spite of guidelines published by US FDA and EU EMA, some open problems on bioequivalence would still require more attention from regulatory authorities, like how to manage the puzzle of endogenous substances, ethical problems against the repeated-dose regimen with some drugs and how to manage Cmax in the presence of the multiple-peak phenomenon.