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

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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.

LanguageEnglish
Article number121741
Number of pages9
JournalJournal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
Volume1126-1127
DOIs
Publication statusPublished - 15 Sep 2019

Fingerprint

Plasmas
Monitoring
Neoplasms
Drug Monitoring
Castration
Prodrugs
Metabolites
Prostatic Neoplasms
Dried Blood Spot Testing
Blood
abiraterone
Pharmaceutical Preparations
Steroid 17-alpha-Hydroxylase
Benchmarking
Pharmacokinetics
Liquid chromatography
Androgen Receptors
Mass spectrometers
Tandem Mass Spectrometry
Mixed Function Oxygenases

Keywords

  • Dried plasma spot
  • Therapeutic drug monitoring
  • Abiraterone
  • ∆(4)-abiraterone
  • Prostate cancer
  • Bioanalysis
  • LC-MS

Cite this

@article{c2ce1b84609d49dd972bde12efec5676,
title = "Bioanalytical evaluation of dried plasma spots for monitoring of abiraterone and ∆(4)-abiraterone from cancer patients",
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 = "Dried plasma spot, Therapeutic drug monitoring, Abiraterone, ∆(4)-abiraterone, Prostate cancer, Bioanalysis, LC-MS",
author = "Atul Bhatnagar and McKay, {Matthew J.} and Morten Thaysen-Andersen and Malmaruha Arasaratnam and Megan Crumbaker and Howard Gurney and Molloy, {Mark P.}",
year = "2019",
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journal = "Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences",
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T1 - Bioanalytical evaluation of dried plasma spots for monitoring of abiraterone and ∆(4)-abiraterone from cancer patients

AU - Bhatnagar,Atul

AU - McKay,Matthew J.

AU - Thaysen-Andersen,Morten

AU - Arasaratnam,Malmaruha

AU - Crumbaker,Megan

AU - Gurney,Howard

AU - Molloy,Mark P.

PY - 2019/9/15

Y1 - 2019/9/15

N2 - 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.

AB - 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.

KW - Dried plasma spot

KW - Therapeutic drug monitoring

KW - Abiraterone

KW - ∆(4)-abiraterone

KW - Prostate cancer

KW - Bioanalysis

KW - LC-MS

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DO - 10.1016/j.jchromb.2019.121741

M3 - Article

VL - 1126-1127

JO - Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences

T2 - Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences

JF - Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences

SN - 1570-0232

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