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Effect of Degarelix, a Gonadotropin-Releasing Hormone Receptor Antagonist for the Treatment of Prostate Cancer, on Cardiac Repolarisation in a Randomised, Placebo and Active Comparator Controlled Thorough QT/QTc Trial in Healthy Men

Olsson, Håkan ; Petri, Niclas ; Erichsen, Lars ; Malmberg, Anders and Grundemar, Lars LU (2017) In Clinical Drug Investigation 37(9). p.873-879
Abstract

BACKGROUND AND OBJECTIVES: Degarelix is a gonadotropin-releasing hormone antagonist registered for the treatment of advanced hormone-dependent prostate cancer. Treatment causing androgen deprivation is associated with QT prolongation and this study investigated whether degarelix at supratherapeutic concentrations has an intrinsic effect per se on cardiac repolarisation and the QT interval.

METHODS: This was a single-centre, randomised, crossover study comparing the effect of degarelix, placebo, and the positive control moxifloxacin on the QT interval. Degarelix and placebo treatments were double-blind, whereas moxifloxacin treatment was open-label. Eighty healthy men, aged 18-45 years, received single intravenous doses of... (More)

BACKGROUND AND OBJECTIVES: Degarelix is a gonadotropin-releasing hormone antagonist registered for the treatment of advanced hormone-dependent prostate cancer. Treatment causing androgen deprivation is associated with QT prolongation and this study investigated whether degarelix at supratherapeutic concentrations has an intrinsic effect per se on cardiac repolarisation and the QT interval.

METHODS: This was a single-centre, randomised, crossover study comparing the effect of degarelix, placebo, and the positive control moxifloxacin on the QT interval. Degarelix and placebo treatments were double-blind, whereas moxifloxacin treatment was open-label. Eighty healthy men, aged 18-45 years, received single intravenous doses of degarelix 2.8 mg, and placebo, as well as a single oral dose of moxifloxacin 400 mg. Electrocardiograms were collected up to 24 h after the start of administration, with the QT interval assessed and plasma concentrations of degarelix concomitantly analysed.

RESULTS: Time-matched, one-sided 95% upper confidence boundaries for baseline-corrected average changes from placebo for the QT interval, corrected using the Fridericia method (ΔΔQTcF), did not exceed 10 ms at any timepoint, with maximum degarelix concentrations reaching approximately threefold the concentrations seen in the treatment of prostate cancer. Furthermore, concentration-exposure analysis indicated absence of any QT prolongation effects of degarelix. No significant effect on any other cardiac parameter was observed. The lower bound of the 98.3% confidence interval for moxifloxacin ΔΔQTcF exceeded 5 ms, thus verifying assay sensitivity.

CONCLUSION: The results showed that the study was validated to detect a significant effect on the QT interval, and that degarelix by itself does not have any effect on the QT interval and cardiac repolarisation at supratherapeutic concentrations.

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author
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Adolescent, Adult, Cross-Over Studies, Double-Blind Method, Electrocardiography, Fluoroquinolones/adverse effects, Humans, Long QT Syndrome/chemically induced, Male, Middle Aged, Moxifloxacin, Oligopeptides/adverse effects, Receptors, LHRH/antagonists & inhibitors, Young Adult
in
Clinical Drug Investigation
volume
37
issue
9
pages
873 - 879
publisher
Adis International
external identifiers
  • scopus:85025117016
  • pmid:28660498
ISSN
1179-1918
DOI
10.1007/s40261-017-0547-7
language
English
LU publication?
no
id
b02686a6-aaa0-48af-a51d-c81ad0b1ba37
date added to LUP
2019-09-03 12:56:40
date last changed
2020-01-16 04:04:27
@article{b02686a6-aaa0-48af-a51d-c81ad0b1ba37,
  abstract     = {<p>BACKGROUND AND OBJECTIVES: Degarelix is a gonadotropin-releasing hormone antagonist registered for the treatment of advanced hormone-dependent prostate cancer. Treatment causing androgen deprivation is associated with QT prolongation and this study investigated whether degarelix at supratherapeutic concentrations has an intrinsic effect per se on cardiac repolarisation and the QT interval.</p><p>METHODS: This was a single-centre, randomised, crossover study comparing the effect of degarelix, placebo, and the positive control moxifloxacin on the QT interval. Degarelix and placebo treatments were double-blind, whereas moxifloxacin treatment was open-label. Eighty healthy men, aged 18-45 years, received single intravenous doses of degarelix 2.8 mg, and placebo, as well as a single oral dose of moxifloxacin 400 mg. Electrocardiograms were collected up to 24 h after the start of administration, with the QT interval assessed and plasma concentrations of degarelix concomitantly analysed.</p><p>RESULTS: Time-matched, one-sided 95% upper confidence boundaries for baseline-corrected average changes from placebo for the QT interval, corrected using the Fridericia method (ΔΔQTcF), did not exceed 10 ms at any timepoint, with maximum degarelix concentrations reaching approximately threefold the concentrations seen in the treatment of prostate cancer. Furthermore, concentration-exposure analysis indicated absence of any QT prolongation effects of degarelix. No significant effect on any other cardiac parameter was observed. The lower bound of the 98.3% confidence interval for moxifloxacin ΔΔQTcF exceeded 5 ms, thus verifying assay sensitivity.</p><p>CONCLUSION: The results showed that the study was validated to detect a significant effect on the QT interval, and that degarelix by itself does not have any effect on the QT interval and cardiac repolarisation at supratherapeutic concentrations.</p>},
  author       = {Olsson, Håkan and Petri, Niclas and Erichsen, Lars and Malmberg, Anders and Grundemar, Lars},
  issn         = {1179-1918},
  language     = {eng},
  number       = {9},
  pages        = {873--879},
  publisher    = {Adis International},
  series       = {Clinical Drug Investigation},
  title        = {Effect of Degarelix, a Gonadotropin-Releasing Hormone Receptor Antagonist for the Treatment of Prostate Cancer, on Cardiac Repolarisation in a Randomised, Placebo and Active Comparator Controlled Thorough QT/QTc Trial in Healthy Men},
  url          = {http://dx.doi.org/10.1007/s40261-017-0547-7},
  doi          = {10.1007/s40261-017-0547-7},
  volume       = {37},
  year         = {2017},
}