Over the last decades, many conferences have been organized to discuss the way in which “a new clinical entity (NCE)” should be tested to successfully pass pharmacology safety requirements. In this editorial, I will concentrate on the repolarization-related concerns, which can be depicted in a number of methodological strategies. Since the introduction of ICH-7B for preclinical work1 and ICH-E14 for the QT-thorough study (QTTS),2 the American and European regulatory offices (FDA-EMEA) have used particularly the latter to make formal decisions on noncardiovascular drugs. Since the first publication in 2007,3 the number of published QTTSs has increased considerably (Fig. 1). This has occurred although the criticism of these guidelines is still strong4 and is, in part, reflected on in this editorial.
In the QTTS, (healthy) volunteers receive the drug to be tested in a random, double-blind, placebo-controlled and in a cross-over design, using at least the therapeutic and a supraclinical dose in comparison with a gold standard like moxifloxacin. In addition, maximal inhibition by drug–drug interaction may be achieved by adding, for instance, ketoconazole, a CYP450/P-gP inhibitor.5,6 The QT(c) interval, recorded digitally, is considered to be a surrogate for drug-induced Torsade de Pointes (TdP) arrhythmias. The warranted increase in QTc duration after moxifloxacin (400 mg, single dose) should be in the range of 5–7 milliseconds (sensitivity control). When this is confirmed, the NCE will be evaluated. Simply stated, a QTc increase of ≤5 milliseconds is considered safe; when a drug increases the QTc between 5 and 15 milliseconds, there is a need for additional (clinical) testing, and when a drug exceeds this limit of a 15-millisecond increase in QT-time, the drug fails this test. Therefore, the conclusion is that a risk exists. Given that approximately 60% of all NCEs do affect the delayed rectifier current (IKr),7 the presumed culprit current responsible for most drug-induced TdP, this kind of testing seems justifiable. Also the notion that drug-induced TdP and sudden cardiac death are not restricted to IKr blockers but may affect other ion currents makes the QTTS a defendable endeavor.
In this issue of the Journal of Cardiovascular Pharmacology,8 the authors have performed such a QTTS quite elegantly using agomelatine, an antidepressant medication. The therapeutic dose of around 50 mg and the supratherapeutic dose of 400 mg had no effect on the QTc interval, whereas moxifloxicin increased QTc by 5–9 milliseconds.
Therefore, when there is concern, these QTTC studies are useful. Concern can be caused due to evidence that the NCE (1) blocks the IKr current, (2) blocks other relevant ion currents, and/or (3) lengthens cardiac APD/QTc in the semitherapeutic range. However, the drug in this particular preclinical study did not raise a (red) flag. At therapeutic plasma concentrations, agomelatine is unlikely to affect cardiac ventricular repolarization: In vitro, agomelatine up to 10 μM (2430 ng/mL) had no significant effect on hERG/IKr or on other ion currents relevant for repolarization, up to 1 μM did not affect APD in canine Purkinje fibers, and in vivo, no QT increases were seen in anesthetized rats or cynomolgus monkeys. In addition, a study in 13 volunteers showed that ≤200 mg (4× therapeutic) agomelatine did not significantly prolong QT/QTc interval in human subjects.8
So questions as: “To what extent are these kinds of costly exercises warranted?”, “Whom are we trying to convince?”, or “How many of these negative studies have to be performed?” become legitimate. Is this mandatory testing going too far? Are we off target?
A task force7 recently suggested that the QTTS be replaced with tests that can be performed earlier, more efficiently, and more accurately. Doing so could increase the number of NCEs that will reach the market. Importantly, this change in direction is not endorsed by the entire safety pharmacology/scientist community. Still it is embraced by some because of the severe restrictions that exist in the current guidelines. It is my belief that it is time to change, even if the aims may still be too ambitious and the limitations large.
1. International Conference on Harmonisation; guidance on S7B Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals; availability. Notice. Fed Regist. 2005;70:61133–61134.
2. International Conference on Harmonisation; guidance on E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs; availability. Notice. Fed Regist. 2005;70:61134–61135.
3. Malhotra BK, Glue P, Sweeney K, et al.. Thorough QT study with recommended and supratherapeutic doses of tolterodine. Clin Pharmacol Ther. 2007;81:377–385.
4. Varkevisser R, Wijers SC, van der Heyden MG, et al.. Beat to beat variability of repolarization as a new biomarker for pro-arrhythmia in vivo. Heart Rhythm. 2012;9:1718–1726.
5. Potkin SG, Preskorn S, Hochfeld M, Meng X. A thorough QTc study of 3 doses of Iloperidone including metabolic inhibition via CYP2D6 and/or CYP3A4 and a comparison to Quetiapine and Ziprasidone. J Clin Psychopharmacol. 2013;33:3–10.
6. Tyl B, Kabbaj M, Azzam S, et al.. Lack of significant effect of bilastine administered at therapeutic and suprathearpeutic doses concomitantly with ketoconazole on ventricular repolarization: results of a QT-thorough QT study (TQTS) with QT-concentration analysis. J Clin Pharmacol. 2012;52:893–903.
7. Sager Ph T, Gintant G, Turner JR, et al.. Rechanneling the cardiac proarrhythmia safety paradigm: a meeting report from the Cardiac Safety Research Consortium. Am Heart J. 2014;167:292–300.
8. Donazzolo Y, Latreille M, Caillaud MA, et al.. Evaluation of the effects of therapeutic and supra-therapeutic doses of agomelatine on the QT/QTc interval—a phase 1, randomised, double blind, placebo controlled and positive controlled, cross over thorough QT/QTc study conducted in healthy volunteers. J Cardiovasc Pharmacol. 2014;64:440–451.