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

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• 作者：James E. Tisdale ; PharmD^a ; ^b ; ^{jtisdale@purdue.edu} ; Heather A. Jaynes ; MSN^a ; Brian R. Overholser ; PharmD^a ; ^b ; Kevin M. Sowinski ; PharmD^a ; ^b ; David A. Flockhart ; MD ; PhD^b ; Richard J. Kovacs ; MD^c
• 关键词：electrocardiography ; hormonal therapy ; QT interval ; torsades de pointes
• 刊名：JACC: Clinical Electrophysiology
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：2
• 期：7
• 页码：765-774
• 全文大小：998 K
• 卷排序：2

文摘

This study tested the hypothesis that oral progesterone administration attenuates drug-induced QT interval lengthening.BackgroundEvidence from preclinical and human investigations suggests that higher serum progesterone concentrations may be protective against drug-induced QT interval lengthening.MethodsIn 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).ResultsFifteen 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.ConclusionsOral progesterone administration attenuates drug-induced QTcI lengthening. (Influence of Progesterone Administration on Drug-Induced QT Interval Lengthening; NCT01929083).