Author + information
- Received November 16, 2015
- Revision received February 8, 2016
- Accepted February 18, 2016
- Published online December 1, 2016.
- James E. Tisdale, PharmDa,b,∗ (, )
- Heather A. Jaynes, MSNa,
- Brian R. Overholser, PharmDa,b,
- Kevin M. Sowinski, PharmDa,b,
- David A. Flockhart, MD, PhDb and
- Richard J. Kovacs, MDc
- aDepartment of Pharmacy Practice, College of Pharmacy, Purdue University, Indianapolis, Indiana
- bDivision of Clinical Pharmacology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana
- cKrannert Institute of Cardiology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana
- ↵∗Reprint requests and correspondence:
Dr. James E. Tisdale, College of Pharmacy, Purdue University, 640 Eskenazi Avenue, Indianapolis, Indiana 46202.
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).
This work was supported by a grant from the American Heart Association Midwest Affiliate (12GRNT12060187). This investigation was also supported by the Clinical Research Center within the Indiana Clinical and Translational Sciences Institute NIH/NCRR grant number UL1TR001108. In addition, this investigation was conducted in a facility constructed with support from Research Facilities Improvement Program grant number C06 RR020128-01 from the National Center for Research Resources, National Institutes of Health. Dr. Overholser was supported in part by National Institutes of Health grant K08 HL095655. Analytical work was performed by the Clinical Pharmacology Analytical Core Laboratory, a core laboratory of the Indiana University Melvin and Bren Simon Cancer Center, supported by the National Cancer Institute grant P30 CA082709. Dr. Kovacs serves as a consultant for Eli Lilly & Company; and is a member of Data Safety Monitoring Boards for Biotie Therapies and Teva Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received November 16, 2015.
- Revision received February 8, 2016.
- Accepted February 18, 2016.
- American College of Cardiology Foundation