TY - JOUR
T1 - Development and Validation of an LC-MS/MS Method for the Simultaneous Quantification of Abiraterone, Enzalutamide, and Their Major Metabolites in Human Plasma
AU - van Nuland, Merel
AU - Hillebrand, Michel J X
AU - Rosing, H.
AU - Schellens, J H M
AU - Beijnen, J H
PY - 2017/6
Y1 - 2017/6
N2 - 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.
AB - 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.
KW - abiraterone
KW - enzalutamide
KW - metabolites
KW - N-desmethylenzalutamide
KW - LC-MS/MS
KW - therapeutic drug monitoring
U2 - 10.1097/FTD.0000000000000387
DO - 10.1097/FTD.0000000000000387
M3 - Article
C2 - 28490047
SN - 0163-4356
VL - 39
SP - 243
EP - 251
JO - Therapeutic Drug Monitoring
JF - Therapeutic Drug Monitoring
IS - 3
ER -
