Influence of Oral Progesterone Administration on Drug-Induced QT Interval Lengthening: A Randomized, Double-Blind, Placebo-Controlled Crossover Study

James E. Tisdale, Heather A. Jaynes, Brian R. Overholser, Kevin M. Sowinski, David A. Flockhart, Richard Kovacs

Research output: Contribution to journalArticle

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Abstract

Objectives This study tested the hypothesis that oral progesterone administration attenuates drug-induced QT interval lengthening. Background Evidence from preclinical and human investigations suggests that higher serum progesterone concentrations may be protective against drug-induced QT interval lengthening. Methods In this prospective, double-blind, crossover study, 19 healthy female volunteers (21 to 40 years of age) were randomized to receive progesterone 400 mg or matching placebo orally once daily for 7 days timed to the menses phase of the menstrual cycle (between-phase washout period = 49 days). On day 7, ibutilide 0.003 mg/kg was infused over 10 min, after which QT intervals were recorded and blood samples collected for 12 h. Before the treatment phases, subjects underwent electrocardiographic monitoring for 12 h to calculate individualized heart rate–corrected QT intervals (QTcI). Results Fifteen subjects completed all study phases. Maximal serum ibutilide concentrations in the progesterone and placebo phases were similar (1,247 ± 770 pg/ml vs. 1,172 ± 709 pg/ml; p = 0.43). Serum progesterone concentrations were higher during the progesterone phase (16.2 ± 11.0 ng/ml vs. 1.2 ± 1.0 ng/ml; p < 0.0001), whereas serum estradiol concentrations in the 2 phases were similar (89.3 ± 62.8 pg/ml vs. 71.8 ± 31.7 pg/ml; p = 0.36). Pre-ibutilide lead II QTcI was significantly lower in the progesterone phase (412 ± 15 ms vs. 419 ± 14 ms; p = 0.04). Maximal ibutilide-associated QTcI (443 ± 17 ms vs. 458 ± 19 ms; p = 0.003), maximal percentage increase in QTcI from pre-treatment value (7.5 ± 2.4% vs. 9.3% ± 3.4%; p = 0.02), and area under the effect (QTcI) curve during the first hour post-ibutilide administration (497 ± 13 ms·h vs. 510 ± 16 ms·h; p = 0.002) were lower during the progesterone phase. Progesterone-associated adverse effects included fatigue/malaise and vertigo. Conclusions Oral progesterone administration attenuates drug-induced QTcI lengthening. (Influence of Progesterone Administration on Drug-Induced QT Interval Lengthening; NCT01929083).

Original languageEnglish (US)
Pages (from-to)765-774
Number of pages10
JournalJACC: Clinical Electrophysiology
Volume2
Issue number7
DOIs
StatePublished - Dec 1 2016

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Progesterone
Oral Administration
Placebos
Pharmaceutical Preparations
Serum
Protective Agents
Menstruation
Vertigo
Menstrual Cycle
Double-Blind Method
Cross-Over Studies
Fatigue
Estradiol
Healthy Volunteers
ibutilide
Therapeutics

Keywords

  • electrocardiography
  • hormonal therapy
  • QT interval
  • torsades de pointes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Influence of Oral Progesterone Administration on Drug-Induced QT Interval Lengthening : A Randomized, Double-Blind, Placebo-Controlled Crossover Study. / Tisdale, James E.; Jaynes, Heather A.; Overholser, Brian R.; Sowinski, Kevin M.; Flockhart, David A.; Kovacs, Richard.

In: JACC: Clinical Electrophysiology, Vol. 2, No. 7, 01.12.2016, p. 765-774.

Research output: Contribution to journalArticle

Tisdale, James E. ; Jaynes, Heather A. ; Overholser, Brian R. ; Sowinski, Kevin M. ; Flockhart, David A. ; Kovacs, Richard. / Influence of Oral Progesterone Administration on Drug-Induced QT Interval Lengthening : A Randomized, Double-Blind, Placebo-Controlled Crossover Study. In: JACC: Clinical Electrophysiology. 2016 ; Vol. 2, No. 7. pp. 765-774.
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abstract = "Objectives This study tested the hypothesis that oral progesterone administration attenuates drug-induced QT interval lengthening. Background Evidence from preclinical and human investigations suggests that higher serum progesterone concentrations may be protective against drug-induced QT interval lengthening. Methods In this prospective, double-blind, crossover study, 19 healthy female volunteers (21 to 40 years of age) were randomized to receive progesterone 400 mg or matching placebo orally once daily for 7 days timed to the menses phase of the menstrual cycle (between-phase washout period = 49 days). On day 7, ibutilide 0.003 mg/kg was infused over 10 min, after which QT intervals were recorded and blood samples collected for 12 h. Before the treatment phases, subjects underwent electrocardiographic monitoring for 12 h to calculate individualized heart rate–corrected QT intervals (QTcI). Results Fifteen subjects completed all study phases. Maximal serum ibutilide concentrations in the progesterone and placebo phases were similar (1,247 ± 770 pg/ml vs. 1,172 ± 709 pg/ml; p = 0.43). Serum progesterone concentrations were higher during the progesterone phase (16.2 ± 11.0 ng/ml vs. 1.2 ± 1.0 ng/ml; p < 0.0001), whereas serum estradiol concentrations in the 2 phases were similar (89.3 ± 62.8 pg/ml vs. 71.8 ± 31.7 pg/ml; p = 0.36). Pre-ibutilide lead II QTcI was significantly lower in the progesterone phase (412 ± 15 ms vs. 419 ± 14 ms; p = 0.04). Maximal ibutilide-associated QTcI (443 ± 17 ms vs. 458 ± 19 ms; p = 0.003), maximal percentage increase in QTcI from pre-treatment value (7.5 ± 2.4{\%} vs. 9.3{\%} ± 3.4{\%}; p = 0.02), and area under the effect (QTcI) curve during the first hour post-ibutilide administration (497 ± 13 ms·h vs. 510 ± 16 ms·h; p = 0.002) were lower during the progesterone phase. Progesterone-associated adverse effects included fatigue/malaise and vertigo. Conclusions Oral progesterone administration attenuates drug-induced QTcI lengthening. (Influence of Progesterone Administration on Drug-Induced QT Interval Lengthening; NCT01929083).",
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T2 - A Randomized, Double-Blind, Placebo-Controlled Crossover Study

AU - Tisdale, James E.

AU - Jaynes, Heather A.

AU - Overholser, Brian R.

AU - Sowinski, Kevin M.

AU - Flockhart, David A.

AU - Kovacs, Richard

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N2 - Objectives This study tested the hypothesis that oral progesterone administration attenuates drug-induced QT interval lengthening. Background Evidence from preclinical and human investigations suggests that higher serum progesterone concentrations may be protective against drug-induced QT interval lengthening. Methods In this prospective, double-blind, crossover study, 19 healthy female volunteers (21 to 40 years of age) were randomized to receive progesterone 400 mg or matching placebo orally once daily for 7 days timed to the menses phase of the menstrual cycle (between-phase washout period = 49 days). On day 7, ibutilide 0.003 mg/kg was infused over 10 min, after which QT intervals were recorded and blood samples collected for 12 h. Before the treatment phases, subjects underwent electrocardiographic monitoring for 12 h to calculate individualized heart rate–corrected QT intervals (QTcI). Results Fifteen subjects completed all study phases. Maximal serum ibutilide concentrations in the progesterone and placebo phases were similar (1,247 ± 770 pg/ml vs. 1,172 ± 709 pg/ml; p = 0.43). Serum progesterone concentrations were higher during the progesterone phase (16.2 ± 11.0 ng/ml vs. 1.2 ± 1.0 ng/ml; p < 0.0001), whereas serum estradiol concentrations in the 2 phases were similar (89.3 ± 62.8 pg/ml vs. 71.8 ± 31.7 pg/ml; p = 0.36). Pre-ibutilide lead II QTcI was significantly lower in the progesterone phase (412 ± 15 ms vs. 419 ± 14 ms; p = 0.04). Maximal ibutilide-associated QTcI (443 ± 17 ms vs. 458 ± 19 ms; p = 0.003), maximal percentage increase in QTcI from pre-treatment value (7.5 ± 2.4% vs. 9.3% ± 3.4%; p = 0.02), and area under the effect (QTcI) curve during the first hour post-ibutilide administration (497 ± 13 ms·h vs. 510 ± 16 ms·h; p = 0.002) were lower during the progesterone phase. Progesterone-associated adverse effects included fatigue/malaise and vertigo. Conclusions Oral progesterone administration attenuates drug-induced QTcI lengthening. (Influence of Progesterone Administration on Drug-Induced QT Interval Lengthening; NCT01929083).

AB - Objectives This study tested the hypothesis that oral progesterone administration attenuates drug-induced QT interval lengthening. Background Evidence from preclinical and human investigations suggests that higher serum progesterone concentrations may be protective against drug-induced QT interval lengthening. Methods In this prospective, double-blind, crossover study, 19 healthy female volunteers (21 to 40 years of age) were randomized to receive progesterone 400 mg or matching placebo orally once daily for 7 days timed to the menses phase of the menstrual cycle (between-phase washout period = 49 days). On day 7, ibutilide 0.003 mg/kg was infused over 10 min, after which QT intervals were recorded and blood samples collected for 12 h. Before the treatment phases, subjects underwent electrocardiographic monitoring for 12 h to calculate individualized heart rate–corrected QT intervals (QTcI). Results Fifteen subjects completed all study phases. Maximal serum ibutilide concentrations in the progesterone and placebo phases were similar (1,247 ± 770 pg/ml vs. 1,172 ± 709 pg/ml; p = 0.43). Serum progesterone concentrations were higher during the progesterone phase (16.2 ± 11.0 ng/ml vs. 1.2 ± 1.0 ng/ml; p < 0.0001), whereas serum estradiol concentrations in the 2 phases were similar (89.3 ± 62.8 pg/ml vs. 71.8 ± 31.7 pg/ml; p = 0.36). Pre-ibutilide lead II QTcI was significantly lower in the progesterone phase (412 ± 15 ms vs. 419 ± 14 ms; p = 0.04). Maximal ibutilide-associated QTcI (443 ± 17 ms vs. 458 ± 19 ms; p = 0.003), maximal percentage increase in QTcI from pre-treatment value (7.5 ± 2.4% vs. 9.3% ± 3.4%; p = 0.02), and area under the effect (QTcI) curve during the first hour post-ibutilide administration (497 ± 13 ms·h vs. 510 ± 16 ms·h; p = 0.002) were lower during the progesterone phase. Progesterone-associated adverse effects included fatigue/malaise and vertigo. Conclusions Oral progesterone administration attenuates drug-induced QTcI lengthening. (Influence of Progesterone Administration on Drug-Induced QT Interval Lengthening; NCT01929083).

KW - electrocardiography

KW - hormonal therapy

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