Bioanalytical evaluation of dried plasma spots for monitoring of abiraterone and ∆(4)-abiraterone from cancer patients

Atul Bhatnagar; Matthew J McKay; Morten Thaysen-Andersen; Malmaruha Arasaratnam; Megan Crumbaker; Howard Gurney; Mark P Molloy

doi:10.1016/j.jchromb.2019.121741

Bioanalytical evaluation of dried plasma spots for monitoring of abiraterone and ∆(4)-abiraterone from cancer patients

J Chromatogr B Analyt Technol Biomed Life Sci. 2019 Sep 15:1126-1127:121741. doi: 10.1016/j.jchromb.2019.121741. Epub 2019 Jul 31.

Authors

Atul Bhatnagar¹, Matthew J McKay², Morten Thaysen-Andersen¹, Malmaruha Arasaratnam³, Megan Crumbaker⁴, Howard Gurney⁵, Mark P Molloy⁶

Affiliations

¹ Department of Molecular Sciences, Macquarie University, Sydney, Australia.
² Department of Molecular Sciences, Macquarie University, Sydney, Australia; Australian Proteome Analysis Facility, Macquarie University, Sydney, Australia.
³ Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, Australia; Department of Clinical Sciences, Macquarie University, Sydney, Australia.
⁴ Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, Australia.
⁵ Department of Clinical Sciences, Macquarie University, Sydney, Australia.
⁶ Department of Molecular Sciences, Macquarie University, Sydney, Australia; Bowel Cancer and Biomarker Laboratory, Kolling Institute, The University of Sydney, Australia. Electronic address: m.molloy@sydney.edu.au.

PMID: 31421381
DOI: 10.1016/j.jchromb.2019.121741

Abstract

Abiraterone acetate is an approved prodrug administered orally in a fixed dose format for the treatment of metastatic castration-resistant prostate cancer (mCRPC). In vivo, the prodrug is readily metabolized to abiraterone and its active metabolite Δ(4)-abiraterone (D4A) which selectively and irreversibly inhibit the 17α-hydroxylase/17,20-lyase (CYP17A1) enzyme and the androgen receptor, respectively. Therapeutic drug monitoring (TDM) of abiraterone and its metabolites may be beneficial as significant pharmacokinetic variability has been observed. Dried plasma spots (DPS) represent an attractive, yet under-utilised approach for TDM analysis with desired features including easy collection, transport, storage and overcomes the issues of blood hematocrit levels known in dried blood spot analysis. In this study we developed and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the simultaneous quantification of abiraterone and D4A with deuterated internal standard (abiraterone D4) from DPS using a high-resolution benchtop mass spectrometer. Calibration curves were linear over a wide and clinically-relevant concentration range (0.132-196.0 ng/mL for abiraterone and 0.110-39.17 ng/mL for D4A) with high accuracy (93-104% for abiraterone and 96-108% for D4A) and precision (%CV ≤ 12.5). As expected, the levels of abiraterone and D4A obtained from DPS from mCRPC patients varied substantially (1.5-31.4 ng/mL for abiraterone and 0.1-5.2 ng/mL for D4A; n = 22). Detailed benchmarking of the DPS method to a pre-validated liquid plasma method showed that the techniques generate quantitative indistinguishable data. Collectively, this demonstrates the potential of using LC-MS/MS in combination with DPS for TDM of abiraterone and D4A from patients.

Keywords: Abiraterone; Bioanalysis; Dried plasma spot; LC-MS; Prostate cancer; Therapeutic drug monitoring; ∆(4)-abiraterone.

MeSH terms

Androstenes / blood*
Androstenes / therapeutic use
Chromatography, Liquid / methods
Dried Blood Spot Testing / methods*
Drug Monitoring / methods*
Humans
Linear Models
Male
Prostatic Neoplasms, Castration-Resistant / drug therapy
Reproducibility of Results
Sensitivity and Specificity
Tandem Mass Spectrometry / methods

Substances

Androstenes
delta4-abiraterone
abiraterone