Inter- and intra-patient variability in pharmacokinetics of abiraterone acetate in metastatic prostate cancer

Malmaruha Arasaratnam, Megan Crumbaker, Atul Bhatnagar, Matthew J. McKay, Mark P. Molloy, Howard Gurney

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Purpose This study examined the inter- and intra-patient variability in pharmacokinetics of AA and its metabolites abiraterone and Δ(4)-abiraterone (D4A), and potential contributing factors.

Methods AA administered daily for ≥4 weeks concurrently with androgen deprivation therapy (ADT) for mCRPC were included. Pharmacokinetic evaluation was performed at two consecutive visits at least 4 weeks apart. Plasma samples were collected 24 h after last dose of AA to obtain drug trough level (DTL) of two active metabolites, abiraterone and D4A.

Results 39 plasma samples were obtained from 22 patients, with 17 patients had repeat DTL measurement. Considerable inter-patient variability in DTL was seen, with initial DTL for abiraterone ranging between 1.5 and 25.4 ng/ml (CV 61%) and for D4A between 0.2 and 2.5 ng/ml (CV 61%). Intra-patient variability in DTL for abiraterone varied between 0.85 and 336% and for D4A between 1.14 and 199%. There was no increase in AA exposure with use of dexamethasone (n = 5; DTL 13.9) compared with prednisone (n = 17; DTL 11.0 p = 0.5), dosing in fasted state (n = 13, DTL 12.1) compared to dosing in fed state (n = 9; DTL 11.1, p = 0.8), or chemotherapy-exposed (n = 10; DTL 8.9) compared to chemotherapy naïve (n = 12; DTL 14.0, p = 0.1).

Conclusions Our cohort demonstrated high inter- and intra-patient variability in both abiraterone and D4A with fixed dosing of AA, with no effect from choice of corticosteroids, prior use of chemotherapy, or dosing in fasting state. Monitoring DTL of AA may be necessary to minimise risk of patients being under-dosed and earlier development of resistance.

LanguageEnglish
Pages139-146
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume84
Issue number1
DOIs
Publication statusPublished - Jul 2019

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Pharmacokinetics
Prostatic Neoplasms
Pharmaceutical Preparations
Chemotherapy
Drug Therapy
Metabolites
Abiraterone Acetate
Plasmas
Level measurement
Drug Monitoring
Prednisone
Dexamethasone
Androgens
abiraterone
Fasting
Adrenal Cortex Hormones

Keywords

  • Abiraterone
  • D4A
  • Pharmacokinetics
  • Prostate cancer

Cite this

@article{b38f2668e2f94ea5b7cd4f71866137cb,
title = "Inter- and intra-patient variability in pharmacokinetics of abiraterone acetate in metastatic prostate cancer",
abstract = "Purpose This study examined the inter- and intra-patient variability in pharmacokinetics of AA and its metabolites abiraterone and Δ(4)-abiraterone (D4A), and potential contributing factors. Methods AA administered daily for ≥4 weeks concurrently with androgen deprivation therapy (ADT) for mCRPC were included. Pharmacokinetic evaluation was performed at two consecutive visits at least 4 weeks apart. Plasma samples were collected 24 h after last dose of AA to obtain drug trough level (DTL) of two active metabolites, abiraterone and D4A. Results 39 plasma samples were obtained from 22 patients, with 17 patients had repeat DTL measurement. Considerable inter-patient variability in DTL was seen, with initial DTL for abiraterone ranging between 1.5 and 25.4 ng/ml (CV 61{\%}) and for D4A between 0.2 and 2.5 ng/ml (CV 61{\%}). Intra-patient variability in DTL for abiraterone varied between 0.85 and 336{\%} and for D4A between 1.14 and 199{\%}. There was no increase in AA exposure with use of dexamethasone (n = 5; DTL 13.9) compared with prednisone (n = 17; DTL 11.0 p = 0.5), dosing in fasted state (n = 13, DTL 12.1) compared to dosing in fed state (n = 9; DTL 11.1, p = 0.8), or chemotherapy-exposed (n = 10; DTL 8.9) compared to chemotherapy na{\"i}ve (n = 12; DTL 14.0, p = 0.1). Conclusions Our cohort demonstrated high inter- and intra-patient variability in both abiraterone and D4A with fixed dosing of AA, with no effect from choice of corticosteroids, prior use of chemotherapy, or dosing in fasting state. Monitoring DTL of AA may be necessary to minimise risk of patients being under-dosed and earlier development of resistance.",
keywords = "Abiraterone, D4A, Pharmacokinetics, Prostate cancer",
author = "Malmaruha Arasaratnam and Megan Crumbaker and Atul Bhatnagar and McKay, {Matthew J.} and Molloy, {Mark P.} and Howard Gurney",
year = "2019",
month = "7",
doi = "10.1007/s00280-019-03862-x",
language = "English",
volume = "84",
pages = "139--146",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer, Springer Nature",
number = "1",

}

Inter- and intra-patient variability in pharmacokinetics of abiraterone acetate in metastatic prostate cancer. / Arasaratnam, Malmaruha; Crumbaker, Megan; Bhatnagar, Atul; McKay, Matthew J.; Molloy, Mark P.; Gurney, Howard.

In: Cancer Chemotherapy and Pharmacology, Vol. 84, No. 1, 07.2019, p. 139-146.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Inter- and intra-patient variability in pharmacokinetics of abiraterone acetate in metastatic prostate cancer

AU - Arasaratnam, Malmaruha

AU - Crumbaker, Megan

AU - Bhatnagar, Atul

AU - McKay, Matthew J.

AU - Molloy, Mark P.

AU - Gurney, Howard

PY - 2019/7

Y1 - 2019/7

N2 - Purpose This study examined the inter- and intra-patient variability in pharmacokinetics of AA and its metabolites abiraterone and Δ(4)-abiraterone (D4A), and potential contributing factors. Methods AA administered daily for ≥4 weeks concurrently with androgen deprivation therapy (ADT) for mCRPC were included. Pharmacokinetic evaluation was performed at two consecutive visits at least 4 weeks apart. Plasma samples were collected 24 h after last dose of AA to obtain drug trough level (DTL) of two active metabolites, abiraterone and D4A. Results 39 plasma samples were obtained from 22 patients, with 17 patients had repeat DTL measurement. Considerable inter-patient variability in DTL was seen, with initial DTL for abiraterone ranging between 1.5 and 25.4 ng/ml (CV 61%) and for D4A between 0.2 and 2.5 ng/ml (CV 61%). Intra-patient variability in DTL for abiraterone varied between 0.85 and 336% and for D4A between 1.14 and 199%. There was no increase in AA exposure with use of dexamethasone (n = 5; DTL 13.9) compared with prednisone (n = 17; DTL 11.0 p = 0.5), dosing in fasted state (n = 13, DTL 12.1) compared to dosing in fed state (n = 9; DTL 11.1, p = 0.8), or chemotherapy-exposed (n = 10; DTL 8.9) compared to chemotherapy naïve (n = 12; DTL 14.0, p = 0.1). Conclusions Our cohort demonstrated high inter- and intra-patient variability in both abiraterone and D4A with fixed dosing of AA, with no effect from choice of corticosteroids, prior use of chemotherapy, or dosing in fasting state. Monitoring DTL of AA may be necessary to minimise risk of patients being under-dosed and earlier development of resistance.

AB - Purpose This study examined the inter- and intra-patient variability in pharmacokinetics of AA and its metabolites abiraterone and Δ(4)-abiraterone (D4A), and potential contributing factors. Methods AA administered daily for ≥4 weeks concurrently with androgen deprivation therapy (ADT) for mCRPC were included. Pharmacokinetic evaluation was performed at two consecutive visits at least 4 weeks apart. Plasma samples were collected 24 h after last dose of AA to obtain drug trough level (DTL) of two active metabolites, abiraterone and D4A. Results 39 plasma samples were obtained from 22 patients, with 17 patients had repeat DTL measurement. Considerable inter-patient variability in DTL was seen, with initial DTL for abiraterone ranging between 1.5 and 25.4 ng/ml (CV 61%) and for D4A between 0.2 and 2.5 ng/ml (CV 61%). Intra-patient variability in DTL for abiraterone varied between 0.85 and 336% and for D4A between 1.14 and 199%. There was no increase in AA exposure with use of dexamethasone (n = 5; DTL 13.9) compared with prednisone (n = 17; DTL 11.0 p = 0.5), dosing in fasted state (n = 13, DTL 12.1) compared to dosing in fed state (n = 9; DTL 11.1, p = 0.8), or chemotherapy-exposed (n = 10; DTL 8.9) compared to chemotherapy naïve (n = 12; DTL 14.0, p = 0.1). Conclusions Our cohort demonstrated high inter- and intra-patient variability in both abiraterone and D4A with fixed dosing of AA, with no effect from choice of corticosteroids, prior use of chemotherapy, or dosing in fasting state. Monitoring DTL of AA may be necessary to minimise risk of patients being under-dosed and earlier development of resistance.

KW - Abiraterone

KW - D4A

KW - Pharmacokinetics

KW - Prostate cancer

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U2 - 10.1007/s00280-019-03862-x

DO - 10.1007/s00280-019-03862-x

M3 - Article

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T2 - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

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