The significance of QT interval in drug development

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 on the drug 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 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 a of The is into 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. For drugs, the is and can from 1 in (e.g. to 1 in (e.g. depending on clinical the of this effect with drugs is to This is the of this an which is not in or when in a not TdP can be in a with of as or to a in the in there is a of by More the effect is not as iatrogenic and it is rate is of the of when as This well by the preceding the withdrawal of the of TdP or QTc interval ms is and that which can be by the of the clinical that is in the regulatory The is that the risk has been during the use of the drugs it is the of the disease in many and the potential for a fatal that an adverse and the need to balance the potential risk the potential during the clinical development of a drug include or are to the potential of a drug to A of will an which at the rate of 1 in and almost that with a of 1 in or less of and of not include at of the drug or the incidence of an adverse (e.g. TdP or QTc interval prolongation to proarrhythmic to be is of the of 1 in and the incidence of the to be when is 1 in the of in the have to it is and in the of a or to have to a clinical of of and/or the duration of an for a is Thus, to the clinical risk of proarrhythmias, the regulatory the surrogate QTc prolongation it is and during drug development. The of development include a drug at than intended therapeutic to a potential and to also in the of of the to any potential of the drug on A of drugs as and have had their potential to prolong the QTc interval and TdP as a result of drugs many with a potential to prolong the QTc interval) are by The activity of this is also to TdP in with the clinical use of these drugs has been most frequently following their use with of as and risk factors are disease (e.g. with and (e.g. with of and the of For is as an is of the blocking in the has been for clinical use and is on the This with the of and of the are as the potential to prolong the QTc interval is present in and the is in of and has a with following therapeutic the of this can be higher than that of with for and for the proarrhythmic activity of during clinical use from the of this in the of has been to have a lower proarrhythmic at than the drug Thus, as with is to and to prolongation of QTc interval is a A adverse can be by an of the drug with or is associated with at a it has a many is that with potential has a than the of a of A to at a for 1 followed by had to be to the following of is drug which has a of in most This is as as in some in the absence of any of It at a of with a slow to a of the to the slow and the to 60 the use of in in the had to be in following the of during of to of QTc interval prolongation and the to an of 2 with a very to a of the is not for use in in the pharmacological activity of a of drugs at pharmacological is well For example, of the of β-adrenoceptor and calcium channel is exclusively or in activity at potassium has also been for the of some drugs. include and The proarrhythmic activity of has been to in This is not it is to proarrhythmic activity in as an drug as as it in for following the of and associated with use there is on other has been to be is an increasing to development of of racemic drugs. This is not potential of the clinical of a for clinical use of the drug in individuals in a is in the This may also be less to with which may also to be an in the are to be other from early clinical aimed at for clinical use that the of this may use in over potential to prolong the QTc interval at the this to the of clinical development of this the of QTc interval prolongation by drugs, can be at and a the of a of QTc drugs, the and is the of a drug that is in the include and The QTc interval prolongation following the administration of has been to with it that of and may also be by The of this polymorphic in the that can be into or by the of disease or during administration of drugs that drug frequently and with from is in known to have of a mutations of potassium resulting in diminished repolarization are and these result in an of the to proarrhythmias. prolongation of QT interval at to be a for the of these there is that these mutations may be and many of the individuals have a normal are at an is also at a risk which is during is a of other clinical with to proarrhythmic QTc interval prolongation QT are associated and have been as risk for ventricular in a of include as and a of as well as for example, myocardial syndrome autonomic and a of other associated with autonomic is associated with of potassium and the of this disease or is used to the iatrogenic of in QT drugs. 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The other the for on the of Regulatory expectations in these have drug development and have activity. The clinical and for the potential of drugs to QTc interval prolongation and potentially fatal TdP have been in an have been a new is to the of drugs associated with QT syndrome and de pointes this of the of this is is that of TdP will be because it is a A may not be at risk when is and may at risk because It is that when or activity are the risk of prolongation of repolarization is The of be in the as a new are for and in the of drugs with known repolarization activity be preclinical have not been of the this may be because of the and to there are also the regulatory issues from the of from the use of to a for the of that can be is a of issues in many the known drugs that prolong the QTc interval and TdP have been to by of the delayed potassium channel. The of a drug that the QTc interval are effect and the of this a the channel for current is by by the on The the channel the a of preparations (e.g. or the ventricular known as in the from or (e.g. it is to the effect of drugs not on the action potential also to the to be by the drug also an of risk factors for TdP that be in in it to not the of the effect of of drugs and the of and drug also other risk factors as myocardial and administration of other drugs known to prolong the QT interval. these be to known to the and QTc interval, to the new drug and/or therapeutic prolongation of the QTc interval is a of the of potassium a preclinical of the effect of the drug on this channel determined the potential of drugs can be in by the of drugs on the of and with clinical changes in and of the drugs associated with QTc prolongation or TdP in and prolongation of the in during slow prolongation at of the drugs not to QTc prolongation and TdP and to with and actually the the prolongation also the of prolongation and this of drugs to QTc syndrome and and of drugs not associated with repolarization to QTc prolongation and 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 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 last of and also during in and for at during and at in the absence and in the of a The of to the for and QT interval corrected by Bazett's and and also by a referred to as a that a and It is to that the used in this not have the to of the of with various QTc interval ms or to the drugs the of clinical it is to a most of the in of and to with to be used by this The of and be addressed include mutations of drug which of or of potassium that the repolarization The be at of the drug and/or there is or any to prolongation of the QT interval, increasing the of the clinical may be in to the risk of QT prolongation by an be for example, when it is associated with proarrhythmic as a chemical or data from it to a pharmacological class or during clinical trials. a regulatory a of factors it to the proarrhythmic of in QTc interval following administration of a new from the of the drug in repolarization to in the pharmacological the proarrhythmic risk from prolongation of the QT interval is by other of the in the of the effect of a drug on it to data on QTc interval. include the duration of the and of in are by in the the of data from clinical the data the and changes from some have from to QTc interval have in QTc interval the interval. drug may also of potassium the effect of is the effect on QTc interval and not the effect at of the For 60 the is ms the over the interval is have from to of of the drug or of the data on some of the most drugs is and in QTc interval and ms following of and and and ms following of racemic and of the QTc interval by 15 ms at and by ms at to This with in the QTc interval of 15 ms following a of and of ms following a of to of QTc interval by ms that of for the QTc interval by there to or age of the of and 60 ms in QTc interval following of and of to with a in QTc interval of ms following in III a for the QTc interval by ms at and ms at The in QTc interval or not ms following administration of for 2 The in QTc interval at to be ms following and ms following the of of The in data on changes from when or evaluating drugs are A to to include and and to for drug in some individuals has to For example, at the on the following data for by the of a of the effect of on QTc interval referred to in QTc interval at as ms ms ms ms ms and ms 15 from a of the QT of drugs at their therapeutic on these and other data on drugs, the of the on QTc interval, by the is in changes in effect from may a it is the with interval ms and/or the most on the potential of a drug to prolong the QT interval and changes may changes in individuals of regulatory in the QT interval also in many an drug in a the from clinical are these changes to to of ventricular the in QTc interval by in to ms it had ms in of these is by this which the regulatory to be of changes in that there are changes in QT interval can be that an effect is prolongation of the QT interval may be a in early QT interval may be by a of factors and A to the drug is changes are not in the and in the QT interval frequently, are and have a with drug QTc that in and are a is to be a which normal and with disease the QTc interval at ms in normal and ms in with disease The in QTc on ms in a normal and ms in a with The QTc ms and ms in any normal and with with 60 associated with a QTc of ms in normal and a ms in with disease when the the QTc from the of the in QTc in the to be Because in the also determined in QTc interval with the it that an in QTc of ms or drug is to a drug effect at the It also that the of a ms of over 1 and over there are data on QTc interval, can on the of in the QTc interval which is to a drug data on QT in a to a from are to be have on of TdP associated with in of the in the the in QTc interval from ms in and ms in The QTc interval the drug ms in of the The of the corrected QT interval is by the that in of these had an QT interval than of of the QTc interval ms and this had to ms (by at the of TdP of QT and QTc of TdP on drugs 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 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