Development and Validation of an LC-MS/MS Method for the Simultaneous Quantification of Abiraterone, Enzalutamide, and Their Major Metabolites in Human Plasma

  • Ther Drug Monit. 2017 Jun;39(3):243-251. doi: 10.1097/FTD.0000000000000387.
Merel van Nuland  1 ,  M J X Hillebrand ,  H Rosing ,  J H M Schellens ,  J H Beijnen
Affiliations
  • 1. *Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute and MC Slotervaart;†Division of Clinical Pharmacology, Department of Medical Oncology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands; and‡Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
PMID: 28490047 DOI: 10.1097/FTD.0000000000000387
Abstract

Background: Abiraterone acetate and enzalutamide are 2 novel drugs for the treatment of metastatic castration-resistant prostate Cancer. The metabolism of these drugs is extensive. Major metabolites are N-desmethyl enzalutamide, enzalutamide carboxylic acid, abiraterone N-oxide sulfate, and abiraterone sulfate; of which N-desmethyl enzalutamide is reported to possess antiandrogen capacities. A liquid chromatography-tandem mass spectrometry method for simultaneous quantification of abiraterone, enzalutamide, and the main metabolites has been developed and validated to support therapeutic drug monitoring.

Methods: Human plasma samples of patients treated with abiraterone or enzalutamide were harvested at the clinic and stored at -20°C. Proteins were precipitated by acetonitrile, and the final extract was injected on a Kinetex C18 column and separated with gradient elution. Analytes were detected by liquid chromatography-mass spectrometry (Triple Quad 6500).

Results: The method was validated over various linear ranges: 1-100 ng/mL for abiraterone, 5-500 ng/mL for enzalutamide and enzalutamide carboxylic acid, 10-1000 ng/mL for N-desmethyl enzalutamide, 30-3000 ng/mL for abiraterone N-oxide sulfate, and 100-10,000 ng/mL for abiraterone sulfate. Intra-assay and interassay variabilities were within ±15% of the nominal concentrations for quality control samples at medium and high concentrations and within ±20% at the lower limit of quantification, respectively.

Conclusions: The described method for simultaneous determination of abiraterone and enzalutamide was validated successfully and provides a useful tool for therapeutic drug monitoring in patients treated with these agents.

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