Plasma Protein Binding of Challenging Compounds. Issue 8 (2nd June 2015)

• Record Type: Journal Article
• Authors: Riccardi, Keith; Cawley, Shannon; Yates, Phillip D.; Chang, Cheng; Funk, Carrie; Niosi, Mark; Lin, Jian; Di, Li
• Is Part Of: Journal of pharmaceutical sciences. Volume 104:Issue 8(2015:Aug.)
• Page Start: 2627
• Page End: 2636
• Publication Date: 2015-06-02
• Subjects: Pharmacy -- Periodicals; 615.1
• DOI: 10.1002/jps.24506
• Languages: English
• ISSNs: 0022-3549

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Accurately determining fraction unbound (<italic>f</italic><sub>u</sub>) with currently available methods has been challenging for certain compounds. Inaccurate <italic>f</italic><sub>u</sub> values can lead to the misinterpretation of important attributes of a drug candidate. Our analysis of over 2000 Pfizer drug discovery compounds showed no systematic bias in low or high <italic>f</italic><sub>u</sub> precision using the equilibrium dialysis method. However, the accuracy of the plasma protein binding (PPB) estimate for highly bound compounds may be poor, should equilibrium not be fully achieved in the equilibrium dialysis assay. Here, a dilution method and a presaturation method were applied to accelerate equilibration for a set of challenging compounds. These improved methods demonstrate the ability to provide an accurate measurement of PPB for highly bound compounds with <italic>f</italic><sub>u</sub> values much less than 1%. Therefore, we recommend that the actual experimental <italic>f</italic><sub>u</sub> value be used for the prediction of drug–drug interaction potential and for the characterization of important drug candidate properties. Our recommendation calls into question the need for current regulatory guidelines that restrict the reporting of <italic>f</italic><sub>u</sub> values below 1%. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:2627–2636, 2015</p> </abstract>