title: Sensitivity-based analytical approaches to support human absolute bioavailability studies.
abstract: The characterization of absolute bioavailability (BA) is useful for non-intravenous (iv.) formulations during drug development and is required by some health authorities. A study design of co-administrating an iv. isotopically labeled microdose with a therapeutic oral dose is a viable approach for the determination of human PK and has been accepted by regulatory agencies. The implementation of an iv.-microdose with oral therapeutic dose in absolute BA studies speeds up clinical development. In recent years, AMS to measure a radiolabeled microdose has been utilized to support several clinical absolute BA studies. An alternative approach for conducting microdose studies is using LC-MS/MS alone to quantitate both the iv. drug and the oral drug. Because both labeled and unlabeled drugs can be measured simultaneously with LC-MS/MS, it is cost effective. However, for compounds with high volume of distribution and/or poor LC-MS/MS response, AMS still provides a superior LLOQ. In this Perspective, we discuss a paradigm for selecting either an LC-MS/MS or AMS-based approach for generating concentration data in absolute BA studies dependent on the required sensitivity.
authors.affiliation: Bristol-Myers Squibb, PO Box 4000, Princeton, NJ 08543, USA.
authors.forename: Xiaohui Sophia
authors.initials: XS
authors.lastname: Xu
authors.forename: Hao
authors.initials: H
authors.lastname: Jiang
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Christopher
authors.forename: Jim X
authors.initials: JX
authors.lastname: Shen
authors.forename: Jianing
authors.initials: J
authors.lastname: Zeng
authors.forename: Mark E
authors.initials: ME
authors.lastname: Arnold
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics; D000284:Administration, Oral; D001682:Biological Availability; D002250:Carbon Radioisotopes / Q000737:chemistry; D002853:Chromatography, Liquid; D004151:Dipeptides / Q000737:chemistry / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D007275:Injections, Intravenous; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
chemical_list: D002250:Carbon Radioisotopes; D004151:Dipeptides; D004791:Enzyme Inhibitors; D004364:Pharmaceutical Preparations; C502994:saxagliptin; D000218:Adamantane