Synergic development of pharmacokinetics and bioanalytical methods as support of pharmaceutical research

The development of pharmacokinetics led this science to achieve a relevant role in the investigation of new chemical
entities for therapeutic application, and has allowed a series of new useful realizations of out of patent drugs like
prolonged release and delayed release formulations, therapeutic delivery system (TDS) for drugs to be active in systemic
circulation avoiding the first pass effect, orodispersible and effervescent formulations, intramuscular and subcutaneous
depot formulations acting over a long period, oral inhalatory systems, and drug association at fixed dose. The above
applications had pharmacokinetics as protagonist and have required the support from bioanalytical methods to assay
drug concentrations, even in pg·mL
−1
of plasma, that really have paralleled the synergic development of pharmacokinetics.
The complexity of the above realizations required specific guidelines from the regulatory authorities, mainly the US
FDA and EU EMA, which have normalized and, in most cases, simplified the above applications admitting some waivers
of in vivobioequivalence.
However, this review highlights some critical points, not yet focused on by operating guidelines, which need to be
clarified by regulatory authorities. One of the most relevant issues is about the planning and conducting bioavailability
and bioequivalence trials with endogenous substances, that possess own homeostatic equilibria with fluctuations, in some
cases with specific rhythms, like melatonin and female sex hormones. The baseline subtraction required by guidelines to define the net contribute to the exogenous absorbed drug in most cases is a non-solvable problem.