Simultaneous quantitation of abiraterone, enzalutamide,N-desmethyl enzalutamide, and bicalutamide in human plasma by LC–MS/MS

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Inhibiting the androgen receptor (AR) pathway is an important clinical strategy in metastatic prostate cancer. Novel agents including abiraterone acetate and enzalutamide have been shown to prolong life in men with metastatic, castration-resistant prostate cancer (mCRPC). To evaluate the pharmacokinetics of AR-targeted agents, we developed and validated an LC–MS/MS assay for the quantitation of enzalutamide, N-desmethyl enzalutamide, abiraterone and bicalutamide in 0.05 mL human plasma. After protein precipitation, chromatographic separation was achieved with a Phenomenex Synergi Polar-RP column and a linear gradient of 0.1% formic acid in methanol and water. Detection with an ABI 4000Q mass spectrometer utilized electrospray ionization in positive multiple reaction monitoring mode. The assay was linear over the ranges of 1–1000 ng/mL for abiraterone and bicalutamide and 100–30,000 ng/mL for N-desmethyl enzalutamide and enzalutamide and proved to be accurate (92.8–107.7%) and precise (largest was 15.3% CV at LLOQ for bicalutamide), and fulfilled FDA criteria for bioanalytical method validation. We demonstrated the suitability of this assay in plasma from patients who were administered enzalutamide 160 mg, abiraterone 1000 mg and bicalutamide 50 mg once a day as monotherapy or in combination. The LC–MS/MS assay that has been developed will be an essential tool that further defines the pharmacology of the combinations of androgen synthesis or AR-receptor targeted agents.

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