Effect of abiraterone acetate plus prednisone on the QT interval in patients with metastatic castration-resistant prostate cancer

A. W. Tolcher, K. N. Chi, N. D. Shore, Roberto Pili, A. Molina, M. Acharya, T. Kheoh, J. J. Jiao, M. Gonzalez, A. Trinh, C. Pankras, N. Tran

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Purpose Abiraterone is the active metabolite of the pro-drug abiraterone acetate (AA) and a selective inhibitor of CYP17, a key enzyme in testosterone synthesis, and improves overall survival in postdocetaxel metastatic castration- resistant prostate cancer (mCRPC). This open-label, single-arm phase 1b study was conducted to assess the effect of AA and abiraterone on the QT interval. Methods The study was conducted in 33 patients with mCRPC. Patients received AA 1,000 mg orally once daily + prednisone 5 mg orally twice daily. Electrocardiograms (ECGs) were collected in triplicate using 12-lead Holter monitoring. Baseline ECGs were obtained on Cycle 1 Day-1. Serial ECG recordings and time-matched pharmacokinetic (PK) blood samples were collected over 24 h on Cycle 1 Day 1 and Cycle 2 Day 1. Serial PK blood samples were also collected over 24 h on Cycle 1 Day 8. Results After AA administration, the upper bound of the 2-sided 90 % confidence interval (CI) for the mean baseline- adjusted QTcF change was < 10 ms; no patients discontinued due to QTc prolongation or adverse events. No apparent relationship between change in QTcF and abiraterone plasma concentrations was observed [estimated slope (90 % CI): 0.0031 (-0.0040, 0.0102)]. Conclusions There is no significant effect of AA plus prednisone on the QT/QTc interval in patients with mCRPC.

Original languageEnglish (US)
Pages (from-to)305-313
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume70
Issue number2
DOIs
StatePublished - Aug 2012
Externally publishedYes

Fingerprint

Castration
Prednisone
Prostatic Neoplasms
Electrocardiography
Pharmacokinetics
Blood
Confidence Intervals
Steroid 17-alpha-Hydroxylase
Ambulatory Electrocardiography
Prodrugs
Metabolites
Testosterone
Labels
Abiraterone Acetate
Plasmas
Survival
Monitoring
Enzymes
abiraterone

Keywords

  • Abiraterone acetate
  • Castration-resistant prostate cancer
  • Pharmacokinetics
  • Phase 1
  • QT interval

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

Effect of abiraterone acetate plus prednisone on the QT interval in patients with metastatic castration-resistant prostate cancer. / Tolcher, A. W.; Chi, K. N.; Shore, N. D.; Pili, Roberto; Molina, A.; Acharya, M.; Kheoh, T.; Jiao, J. J.; Gonzalez, M.; Trinh, A.; Pankras, C.; Tran, N.

In: Cancer Chemotherapy and Pharmacology, Vol. 70, No. 2, 08.2012, p. 305-313.

Research output: Contribution to journalArticle

Tolcher, AW, Chi, KN, Shore, ND, Pili, R, Molina, A, Acharya, M, Kheoh, T, Jiao, JJ, Gonzalez, M, Trinh, A, Pankras, C & Tran, N 2012, 'Effect of abiraterone acetate plus prednisone on the QT interval in patients with metastatic castration-resistant prostate cancer', Cancer Chemotherapy and Pharmacology, vol. 70, no. 2, pp. 305-313. https://doi.org/10.1007/s00280-012-1916-9
Tolcher, A. W. ; Chi, K. N. ; Shore, N. D. ; Pili, Roberto ; Molina, A. ; Acharya, M. ; Kheoh, T. ; Jiao, J. J. ; Gonzalez, M. ; Trinh, A. ; Pankras, C. ; Tran, N. / Effect of abiraterone acetate plus prednisone on the QT interval in patients with metastatic castration-resistant prostate cancer. In: Cancer Chemotherapy and Pharmacology. 2012 ; Vol. 70, No. 2. pp. 305-313.
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abstract = "Purpose Abiraterone is the active metabolite of the pro-drug abiraterone acetate (AA) and a selective inhibitor of CYP17, a key enzyme in testosterone synthesis, and improves overall survival in postdocetaxel metastatic castration- resistant prostate cancer (mCRPC). This open-label, single-arm phase 1b study was conducted to assess the effect of AA and abiraterone on the QT interval. Methods The study was conducted in 33 patients with mCRPC. Patients received AA 1,000 mg orally once daily + prednisone 5 mg orally twice daily. Electrocardiograms (ECGs) were collected in triplicate using 12-lead Holter monitoring. Baseline ECGs were obtained on Cycle 1 Day-1. Serial ECG recordings and time-matched pharmacokinetic (PK) blood samples were collected over 24 h on Cycle 1 Day 1 and Cycle 2 Day 1. Serial PK blood samples were also collected over 24 h on Cycle 1 Day 8. Results After AA administration, the upper bound of the 2-sided 90 {\%} confidence interval (CI) for the mean baseline- adjusted QTcF change was < 10 ms; no patients discontinued due to QTc prolongation or adverse events. No apparent relationship between change in QTcF and abiraterone plasma concentrations was observed [estimated slope (90 {\%} CI): 0.0031 (-0.0040, 0.0102)]. Conclusions There is no significant effect of AA plus prednisone on the QT/QTc interval in patients with mCRPC.",
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author = "Tolcher, {A. W.} and Chi, {K. N.} and Shore, {N. D.} and Roberto Pili and A. Molina and M. Acharya and T. Kheoh and Jiao, {J. J.} and M. Gonzalez and A. Trinh and C. Pankras and N. Tran",
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AU - Tolcher, A. W.

AU - Chi, K. N.

AU - Shore, N. D.

AU - Pili, Roberto

AU - Molina, A.

AU - Acharya, M.

AU - Kheoh, T.

AU - Jiao, J. J.

AU - Gonzalez, M.

AU - Trinh, A.

AU - Pankras, C.

AU - Tran, N.

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N2 - Purpose Abiraterone is the active metabolite of the pro-drug abiraterone acetate (AA) and a selective inhibitor of CYP17, a key enzyme in testosterone synthesis, and improves overall survival in postdocetaxel metastatic castration- resistant prostate cancer (mCRPC). This open-label, single-arm phase 1b study was conducted to assess the effect of AA and abiraterone on the QT interval. Methods The study was conducted in 33 patients with mCRPC. Patients received AA 1,000 mg orally once daily + prednisone 5 mg orally twice daily. Electrocardiograms (ECGs) were collected in triplicate using 12-lead Holter monitoring. Baseline ECGs were obtained on Cycle 1 Day-1. Serial ECG recordings and time-matched pharmacokinetic (PK) blood samples were collected over 24 h on Cycle 1 Day 1 and Cycle 2 Day 1. Serial PK blood samples were also collected over 24 h on Cycle 1 Day 8. Results After AA administration, the upper bound of the 2-sided 90 % confidence interval (CI) for the mean baseline- adjusted QTcF change was < 10 ms; no patients discontinued due to QTc prolongation or adverse events. No apparent relationship between change in QTcF and abiraterone plasma concentrations was observed [estimated slope (90 % CI): 0.0031 (-0.0040, 0.0102)]. Conclusions There is no significant effect of AA plus prednisone on the QT/QTc interval in patients with mCRPC.

AB - Purpose Abiraterone is the active metabolite of the pro-drug abiraterone acetate (AA) and a selective inhibitor of CYP17, a key enzyme in testosterone synthesis, and improves overall survival in postdocetaxel metastatic castration- resistant prostate cancer (mCRPC). This open-label, single-arm phase 1b study was conducted to assess the effect of AA and abiraterone on the QT interval. Methods The study was conducted in 33 patients with mCRPC. Patients received AA 1,000 mg orally once daily + prednisone 5 mg orally twice daily. Electrocardiograms (ECGs) were collected in triplicate using 12-lead Holter monitoring. Baseline ECGs were obtained on Cycle 1 Day-1. Serial ECG recordings and time-matched pharmacokinetic (PK) blood samples were collected over 24 h on Cycle 1 Day 1 and Cycle 2 Day 1. Serial PK blood samples were also collected over 24 h on Cycle 1 Day 8. Results After AA administration, the upper bound of the 2-sided 90 % confidence interval (CI) for the mean baseline- adjusted QTcF change was < 10 ms; no patients discontinued due to QTc prolongation or adverse events. No apparent relationship between change in QTcF and abiraterone plasma concentrations was observed [estimated slope (90 % CI): 0.0031 (-0.0040, 0.0102)]. Conclusions There is no significant effect of AA plus prednisone on the QT/QTc interval in patients with mCRPC.

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KW - Phase 1

KW - QT interval

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