Overcoming the stability, solubility and extraction challenges in reversed-phase UHPLC-MS/MS bioanalysis of a phosphate drug and its prodrug in blood lysate

Journal of Pharmaceutical and Biomedical Analysis
Long YuanQin C Ji

Abstract

BMS-986104 is a S1P1R modulator drug candidate under development and has been evaluated in Phase I clinical trials. BMS-986104 functions as a prodrug and undergoes enzymatic transformations in vivo to form the pharmacologically active phosphate drug, BMS-986104-P. Here, we report approaches to overcome the stability, solubility and extraction challenges in developing a sensitive, accurate and rugged LC-MS/MS method for the simultaneous quantification of the phosphate drug and its prodrug in blood lysate. An effective stabilization strategy using a cocktail of phosphatase and kinase inhibitors was developed to ensure the stability of both analytes during sample collection, storage, and processing. A combination of surfactant (CHAPS) and weak base (Tris) was found to be able to effectively improve the solubilization of the phosphate drug. The blood lysate samples were extracted by protein precipitation followed by solid-phase extraction using an Oasis HLB 96-well SPE plate. The method achieved acceptable matrix effect and recovery for the two analytes that have very different chemical properties. Stable-isotope labeled D6-BMS-986104 and D13-BMS-986104-P were utilized as the internal standards. Chromatographic separation was achie...Continue Reading

Citations

Apr 21, 2020·Expert Opinion on Investigational Drugs·Shalabh SinghalJohn Throup

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