title: Synergic development of pharmacokinetics and bioanalytical methods as support of pharmaceutical research.
abstract: 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 vivo bioequivalence.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.
authors.affiliation: Department of Medical, Oral e Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, Via dei Vestini 31, I-66013, Chieti, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Marzo
authors.affiliation: Department of Medical, Oral e Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, Via dei Vestini 31, I-66013, Chieti, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Ciccarelli
authors.affiliation: Department of Medical, Oral e Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, Via dei Vestini 31, I-66013, Chieti, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Di Iorio
authors.affiliation: Department of Medical, Oral e Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, Via dei Vestini 31, I-66013, Chieti, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Giuliani
authors.affiliation: Department of Medical, Oral e Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, Via dei Vestini 31, I-66013, Chieti, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Caciagli
authors.affiliation: Department of Medical, Oral e Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, Via dei Vestini 31, I-66013, Chieti, Italy antoniop.marzo@libero.it.
authors.forename: A
authors.initials: A
authors.lastname: Marzo
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*; D000071220:Pharmaceutical Research / Q000379:methods; D013810:Therapeutic Equivalency; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D004364:Pharmaceutical Preparations
keywords: analytical bioassay methods; bioavailability; bioequivalence; endogenous substances; pharmacokinetics