The significance of QT interval in drug development (2002)

The duration of QT interval of the surface electrocardiogram (ECG) reflects the ventricular action potential duration (APD) which is determined mainly by the rapid component of the outward repolarizing current (IKr). This current is mediated primarily by the delayed rectifying potassium channel. Thus, the QT interval is congenitally prolonged when this current is diminished as a result of genetic mutations of this channel as for example in the Romano–Ward syndrome [1]. Reduction in this current and hence, the prolongation of the QT interval may also be acquired, resulting from electrolyte imbalance (especially hypokalaemia and/or hypomagnesaemia), endocrine dysfunction (e.g. hypothyroidism), autonomic imbalance, various disease states or most frequently, following clinical administration of drugs. Drug-induced prolongation of the QTc interval may be followed by potentially fatal proarrhythmias. More than any other adverse drug reaction in recent times, it has been responsible for the withdrawal of many drugs from the market and yet as a surrogate of proarrhythmias, it is not well understood. Regulatory decisions have resulted in rejection of some new drugs or the restriction on the clinical use of many old and other new drugs over the last decade because of their potential to prolong the QTc interval. Therefore, there are regulatory and clinical expectations of better preapproval characterization of new chemical entities (NCEs) for this potential risk which have had a very profound influence on drug development. This paper will focus on the issues that need to be addressed during drug development, strategies aimed at identifying this risk during early preclinical and clinical phases of drug development and the regulatory assessment of the potential risk, particularly the electrocardiographic data from the clinical trials. Because the actually measured QT interval changes with heart rate in the absence of any intervention, it is usual to correct the measured interval for changes in heart rates (RR interval) to derive a rate-corrected (QTc) interval, which is then used when evaluating the effect of an intervention. Clinically, the rate-correction applied most widely, and almost exclusively for years, is the Bazett's correction (QTc=QT/RR0.50), which divides the measured QT interval by the square root of the preceding RR interval. A less frequently applied rate-correction is that of Fridericia (QTc=QT/RR0.33) which divides the measured QT interval by the cube root of the preceding RR interval. Both these corrections standardize the measured QT interval to an RR interval of 1 s (heart rate of 60 beats min−1). When corrected by Bazett's formula, on historical and epidemiological grounds, the widely accepted upper limits of normal QTc interval are 450 ms in adult males, 470 ms in adult females and 460 ms in children between 1 and 15 years of age (regardless of gender). Unless stated otherwise, the QTc interval referred to in this paper is the interval as corrected by Bazett's formula. Drug-induced prolongation of QTc interval is expected with class III antiarrhythmic drugs which are intended to produce their desired therapeutic benefit by blocking IKr, delaying ventricular repolarization and, therefore, increasing myocardial refractory period. Typical examples of these drugs include sotalol, bretylium, ibutilide, dofetilide, azimilide, sematilide, ambasilide, almokalant, N-acetyl-procainamide, fenoxedil and terikalant. Excessive QTc interval prolongation in the right setting (see risk modifying factors below) can be proarrhythmic and degenerate into a potentially fatal ventricular tachyarrhythmia known as torsade de pointes (TdP), a unique polymorphic form of ventricular tachycardia which (by definition) is associated with concomitant prolongation of QTc interval [2]. TdP is triggered by the appearance of early after-depolarizations (EADs), mediated by slow inward calcium current, during the late phase 2 of the prolonged action potential. Therefore, as an extension of their pharmacological effect, this iatrogenic proarrhythmia may be expected in some individuals following the use of antiarrhythmic drugs, which possess class III (potassium channel blocking) activity. For example, the incidence of TdP is variously estimated to be 0.5% to 8.8% with quinidine [3] and 2.6% to 4.1% with sotalol [4]. The incidence is higher in combination preparations of sotalol that include a thiazide diuretic, which induces hypokalaemia [5], and lower with racemic sotalol in contrast to (+)-(S)-sotalol because of the β-adrenoceptor blocking activity of (−)-(R)-sotalol present in the former. It is plainly evident that the balance between the therapeutic antiarrhythmic effect and the potentially fatal proarrhythmic effect of QTc interval prolongation is a very delicate one, depending not only on the drug concerned and also on a of modifying factors include electrolyte imbalance (especially myocardial heart with or heart and prolongation of QTc interval to a of which is a include and, when the from as and/or TdP into ventricular in of and, not and may be the The is of the of the potential to prolong the QTc interval and TdP is not to class III antiarrhythmic drugs. A of class antiarrhythmic and drugs as well as drugs also this are and well over drugs which have been to prolong the QTc interval and/or there are many other drugs which have been to current in of their the drugs include and and drugs. are also a of drugs as and which are a recent of of TdP in the and the most drugs and the associated with and associated with a fatal The proarrhythmia associated with a in with drug in and with an in of the and drugs, in the and regulatory because of their to produce QTc interval prolongation and/or to and/or during their clinical drugs and for and and and drug for of these drugs have been from the A of new chemical entities example, and have been in or of the because of their potential Therefore, as an adverse effect, the of an for potential to prolong the QTc interval during drug development be the regulatory focus on QTc interval prolongation by drugs has from of a potentially antiarrhythmic to of potentially fatal to the regulatory are the that the of drugs to QTc interval prolongation to many of these drugs are for or risk with for most of these drugs, their potential to prolong the QTc interval and TdP not for many or years the drug and in clinical and the at risk is than had been The regulatory are particularly by the that the to the risk and to the the effect on the duration of QTc interval there almost of this in of the use of drugs or of by as these QT drugs not only the therapeutic also the of clinical in this potentially fatal the of drug and factors that be when The of drugs by therapeutic class a are to have activity at pharmacological other than intended during their development. are known to QTc drugs to a chemical associated with therapeutic have been or used in an therapeutic for example, a aimed at a new because of pharmacological at the development to the as any other drug it because of effect on QTc interval and to to the market in for the of it a and drug from the or use to of TdP primarily resulting from drug or intended for development as an for dysfunction and it is not that many it has been to prolong repolarization by blocking the rapid component of the delayed potassium current, at well only a of The is into only the of the drug is Therefore, a effect on repolarization is most during the therapeutic use of there have been of QTc interval prolongation or TdP following the of this used drug the on regulatory of of drugs by therapeutic of the drugs had potential to prolong the QT interval during the of clinical in the regulatory has been the interval from of almost these drugs to the of their proarrhythmic or QTc potential. from this has from 2 to years for to as as years for The proarrhythmic potential of during clinical trials. the drugs and to prolong QTc interval during clinical trials. a is on the of clinical in or over very during or in during to this The from a regulatory is and these clinical are in this the from in QTc interval and the of the effect The present is primarily responsible for of clinical to the of The of are not are the to the drug during clinical use in at a in these preapproval clinical trials. include with or drugs with a potential for or Thus, the for or in clinical is also very the has that these are the most risk it is that the risk can from to depending on or intervention. The of TdP or prolongation of the QTc interval to a proarrhythmic with the class of drugs. it is the with class III antiarrhythmic drugs. 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prolongation also the of prolongation and this of drugs to QTc syndrome and and of drugs not associated with repolarization to QTc prolongation and only prolonged the in and and effect on from the ventricular at prolongation of and appearance of in preparations and of current of potential clinical risk, it is to in that in these in data to the clinical setting in not be are the of the drug between and the myocardial and any other pharmacological of the (e.g. or calcium channel or or β-adrenoceptor blocking that may the clinical this the clinical development can be to the of in the risk during clinical use of the drug be the of the a at with the for the for This to the risk for many drugs that at only clinical that is that used by the of This referred to as by the in to the potential of for prolongation of the QTc interval to that of other following their This an in with The on and from historical data from with a interval to be a of of and a and to of an and and period. during of the 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as or and drugs as and the the had TdP on and and in this had interval ms to the of The between antiarrhythmic and proarrhythmic of QT interval is well there is that a prolongation of QT interval, corrected for heart ms of particularly when associated with slow heart data also that in an of 60 ms or in or QTc interval over or a QTc interval of ms or of the of from is of the potential is expected to be in any regulatory has been of the of Bazett's correction for heart of Bazett's square root that it at and higher heart rates and, therefore, a the drug when the drug the heart rate as This is only for drugs which have a effect on heart some have a use of is a of over correction have their and is A to be the Fridericia have the use of a correction from of QT interval on heart rate during the of rate correction be to derive correction factors for of the in a It is that correction may be less to the of changes in heart rate and therefore, on which to regulatory decisions on their use may not be of are on with may not be This is well by data with other in the referred to The data are in and the administration of these drugs in the absence of a there changes in heart rates from beats on to beats on as not to of the of the with the drugs, various the that and may have the potential to prolong the QT interval to Bazett's correction not to correction prolonged QT interval and TdP have been with for changes in QTc on these drugs, there is to between any of the most drugs on the heart have a to the heart rate than it as with to the of or the Fridericia correction or the better these the at lower heart rates when the proarrhythmic risk is the of the to these the data on the of with changes in corrected QT interval the QT potential of that of of the correction prolonged QT interval and TdP have been with as well as with and with it is any drug has an adverse regulatory of potential to prolong the QT interval because of any resulting from the used for rate is the of a drug effect on QTc interval on drug to the on the of a It that over the to to have an effect on QTc interval an rate of from development and had as well as drugs a of and chemical and intended to have an effect on it has also evident that when the characterization of the of the new drug has been for some had to be at an of clinical development following a late of this The adverse effect of drugs on QTc interval and the resulting have to be a and regulatory have the that this potential risk will be during the development of the in drug development, it is that this is addressed as early as with a to a or to modifying the clinical development It is not that drugs with a potential to prolong QTc interval may be a clinical development a in the of the drug can be to the potential risk of proarrhythmias, or the drug can be to an For drugs, the on the proarrhythmic risk as well as a of drug and and during clinical to for to use the data from on and to for and