Merel van Nuland1, M J X Hillebrand, H Rosing, J H M Schellens, J H Beijnen. 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.
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.
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.
Authors: Guillemette E Benoist; Eric van der Meulen; Inge M van Oort; Jan H Beumer; Diederik M Somford; Jack A Schalken; David M Burger; Nielka P van Erp Journal: Ther Drug Monit Date: 2018-04 Impact factor: 3.681