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Defining an appropriate and efficient assessment of drug-induced corrected QT interval (QTc) prolongation (a surrogate marker of torsades de pointes arrhythmia) remains a concern of drug developers and regulators worldwide. In use for over 15 years, the nonclinical International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and clinical ICH E14 guidances describe three core assays (S7B: in vitro hERG current & in vivo QTc studies; E14: thorough QT study) that are used to assess the potential of drugs to cause delayed ventricular repolarization. Incorporating these assays during nonclinical or human testing of novel compounds has led to a low prevalence of QTc-prolonging drugs in clinical trials and no new drugs having been removed from the marketplace due to unexpected QTc prolongation. Despite this success, nonclinical evaluations of delayed repolarization still minimally influence ICH E14-based strategies for assessing clinical QTc prolongation and defining proarrhythmic risk. In particular, the value of ICH S7B-based "double-negative" nonclinical findings (low risk for hERG block and in vivo QTc prolongation at relevant clinical exposures) is underappreciated. These nonclinical data have additional value in assessing the risk of clinical QTc prolongation when clinical evaluations are limited by heart rate changes, low drug exposures, or high-dose safety considerations. The time has come to meaningfully merge nonclinical and clinical data to enable a more comprehensive, but flexible, clinical risk assessment strategy for QTc monitoring discussed in updated ICH E14 Questions and Answers. Implementing a fully integrated nonclinical/clinical risk assessment for compounds with double-negative nonclinical findings in the context of a low prevalence of clinical QTc prolongation would relieve the burden of unnecessary clinical QTc studies and streamline drug development., (© 2020 Amgen, Inc.; Pfizer, Inc.; Takeda Inc.; Bayer; Novartis; Merck; Bristol-Myers Squibb; and Janssen. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Teriparatide (recombinant human parathyroid hormone [1-34]) stimulates bone formation and causes small transient increases in serum calcium concentration. We assessed whether teriparatide causes a change in digoxin pharmacodynamic effects by measuring systolic time intervals and heart rate., Methods: Measurements were made by echocardiographic Doppler that examined 3 systolic time intervals, as follows: QS(2) (time from Q wave on electrocardiogram to the closure of the aortic valve), left ventricular ejection time, and pre-ejection period, all corrected for changes in heart rate. Fifteen healthy subjects (2 men and 13 women) were administered a single subcutaneous teriparatide dose (20 microg) on day 1 and then equilibrated on a daily oral dose of digoxin for 15 days. Subcutaneous placebo and teriparatide, 20 microg, were given in a randomized crossover design with the 14th (day 15) and 15th (day 16) digoxin doses. Serial systolic time interval and heart rate measurements were obtained on days 1, 15, and 16., Results: After subjects were dosed to steady state with digoxin, there were statistically significant reductions in QS(2) corrected for heart rate (QS(2)c) of 23 to 25 ms and heart rate of 4 to 6 beats/min. However, there was no difference between treatment with digoxin plus placebo versus digoxin plus teriparatide. The study was powered to find a difference in QS(2)c as small as 6 ms (alpha =.05, beta =.2)., Conclusion: Teriparatide, 20 microg subcutaneously, does not alter the cardiac effect of digoxin.