Xu Xiaohui Sophia, Jiang Hao, Christopher Lisa J, Shen Jim X, Zeng Jianing, Arnold Mark E
Bristol-Myers Squibb, PO Box 4000, Princeton, NJ 08543, USA.
Bioanalysis. 2014 Feb;6(4):497-504. doi: 10.4155/bio.13.318.
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.
绝对生物利用度（BA）的表征在药物研发过程中对非静脉注射制剂很有用，并且是一些卫生当局所要求的。将静脉注射同位素标记的微量剂量与治疗性口服剂量共同给药的研究设计是测定人体药代动力学的一种可行方法，并且已被监管机构接受。在绝对生物利用度研究中采用静脉注射微量剂量与口服治疗剂量的方法可加快临床研发进程。近年来，利用加速器质谱（AMS）来测量放射性标记的微量剂量已被用于支持多项临床绝对生物利用度研究。进行微量剂量研究的另一种方法是仅使用液相色谱-串联质谱（LC-MS/MS）来定量静脉注射药物和口服药物。由于标记药物和未标记药物都可以用LC-MS/MS同时测量，因此具有成本效益。然而，对于分布容积大且/或LC-MS/MS响应差的化合物，AMS仍然提供了更好的最低定量限（LLOQ）。在本观点中，我们讨论了一种范式，即根据所需灵敏度在绝对生物利用度研究中选择基于LC-MS/MS或AMS的方法来生成浓度数据。
