The significance of QT interval in drug development
2002; Wiley; Volume: 54; Issue: 2 Linguagem: Inglês
10.1046/j.1365-2125.2002.01627.x
ISSN1365-2125
Autores Tópico(s)Cardiac Arrhythmias and Treatments
ResumoThe 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 its plasma concentration but also on a number of host modifying factors. These factors include female gender, electrolyte imbalance (especially hypokalaemia), myocardial ischaemia, atrial fibrillation, congestive heart failure, bradycardias with or without heart blocks and pre-existing prolongation of QTc interval [6], to name a few. Clinical manifestations of TdP, which usually is a transient tachyarrhythmia, include palpitation and, when prolonged, the symptoms arising from impaired cerebral circulation such as dizziness, syncope and/or seizures. TdP subsequently degenerates into ventricular fibrillation in about 20% of cases [7] and, not uncommonly, cardiac arrest and sudden death may be the outcome [6]. The overall mortality is of the order of 10–17% [7, 8]. Unfortunately, the potential to prolong the QTc interval and induce TdP is not confined to class III antiarrhythmic drugs. A number of class I antiarrhythmic and antianginal drugs as well as noncardiovascular drugs also carry this liability. There are now about 10 antianginal and well over 90 noncardiac drugs (Table 1), which have been reported to prolong significantly the QTc interval and/or induce TdP. In addition, there are many other drugs which have been shown to block IKr current in vitro. In terms of their pharmacotherapeutic classes, the noncardiac drugs include H1-antihistamines, antidepressants, neuroleptics, antimicrobials including fluoroquinolones and antimalarials, serotonin antagonists and anticancer drugs. There are also a host of miscellaneous drugs such as probucol, cisapride, sevoflurane, bupivacaine, tacrolimus, levacetylmethadol, tiapride, amiloride and lubelozole, which are torsadogenic. In a recent survey of 2194 cases of TdP in the US Food and Drug Administration (FDA) database [8], the most common drugs implicated were cardiac (26.2%), central nervous system (CNS) (21.9%), anti-infectives (19.0%) and antihistamines (11.6%). Of the 2194 cases, 61.1% were associated with hospitalization, 27.9% were life-threatening and 9.8% were associated with a fatal outcome. The proarrhythmia was associated with a serious underlying condition in 16.2%, with drug interactions in 11.7% and with an overdose in 9.2% of the cases. Between June 1990 and March 2001, 11 noncardiac drugs, marketed in the United Kingdom and elsewhere, attracted significant regulatory actions because of their propensity to produce QTc interval prolongation and/or TdP. Their prescribing information was changed substantially to revise dose schedules, contraindications and/or precautions during their clinical use. These drugs included two H1-antihistamines (terfenadine and astemizole), one gastric prokinetic agent (cisapride), one agent for urinary incontinence (terodiline), two anti-infectives (halofantrine and grepafloxacin), four neuroleptics (pimozide, thioridazine, sertindole and droperidol) and one drug for opiate addiction (levacetylmethadol). Eight of these drugs have now been withdrawn from the market. A number of new noncardiovascular chemical entities (for example, gatifloxacin, moxifloxacin and ziprasidone) have been refused approval in one or more of the major markets because of their potential 'QTc liability'. Therefore, as an adverse effect, the significance of investigating an NCE for its potential to prolong the QTc interval during drug development cannot be overemphasized. Not surprisingly, the regulatory focus on QTc interval prolongation by drugs has changed from one of a potentially desirable antiarrhythmic mechanism to one of potentially fatal proclivity. Central to the regulatory concern are the facts that (i) the number of noncardiac drugs recognized to cause QTc interval prolongation continues to increase (ii) many of these drugs are prescribed for otherwise relatively benign or low risk conditions, often with safer alternatives (iii) for most of these drugs, historically, their potential to prolong the QTc interval and induce TdP was not recognized for many months or years after the drug was approved and in clinical use, and finally (iv) the population at risk is greater than had hitherto been appreciated. The regulatory concerns are particularly heightened by the facts that despite the best endeavours to characterize the risk and provide adequate prescribing information to the prescribing physicians, once the effect on the duration of QTc interval was identified, there was almost total disregard of this prescribing information in terms of the concurrent use of contraindicated drugs or monitoring of patients by ECG as recommended [9–12]. Between them, these QT prolonging drugs illustrate not only the diverse therapeutic classes implicated but also the limitations of previously conducted clinical trials in detecting this potentially fatal cardiotoxic effect. They highlight the roles of drug interactions, metabolites, dose schedules, pharmacogenetic traits and stereoselective factors that should be explored thoroughly when developing NCEs. The division of drugs by therapeutic class alone deserves a critical cautionary comment. Drugs are often discovered to have more potent activity at pharmacological targets other than those originally intended during their development. Drugs are therefore known to cross 'therapeutic boundaries'. Many QTc prolonging drugs belong to a specific chemical class, usually associated with one therapeutic area but have later been developed or used clinically in an entirely different therapeutic area (Table 2). Terfenadine, for example, was discovered through a CNS programme aimed at developing a new neuroleptic agent but because of its more potent secondary pharmacological effects at the H1-antihistamine receptor, its development was re-focused to introduce the first nonsedating H1-antihistamine. Not surprisingly, as any other neuroleptic drug might have, it too attracted considerable attention because of its effect on QTc interval and its ability to induce TdP. Introduced to the market in 1982 for the treatment of hayfever, it was a highly successful and popular drug until withdrawn from the market, or its use severely restricted, due to reports of TdP primarily resulting from drug interactions or overdoses. Sildenafil, originally intended for development as an antianginal drug, was developed for male erectile dysfunction and it is not surprising that like many antianginals, it has recently been shown to prolong cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current, albeit at concentrations (IC50=100 µmol l−1) well exceeding those encountered therapeutically (1 µmol l−1) [13]. Even 30 µmol l−1 induced only a 15% blockade of IKr. The margin is even greater if one takes into account only the free fraction of the drug since sildenafil is about 96% protein-bound. Therefore, clearly, a clinically significant effect on repolarization is most unlikely during the therapeutic use of sildenafil [14]. Although there have been no reports of QTc interval prolongation or TdP following the marketing of this intermittently used drug after its approval, sildenafil does illustrate the point being made on regulatory limitations of classification of drugs by therapeutic class. None of the older drugs had declared its potential to prolong the QT interval during the types of clinical trials conducted in the past. Of particular regulatory concern has been the interval from first approval of almost all these drugs to the first identification of their proarrhythmic or QTc prolonging potential. Apart from halofantrine, this has ranged from 2 to 3 years for astemizole to as much as 17 years for pimozide. The proarrhythmic potential of halofantrine was strongly signalled during its clinical trials. Among the drugs developed recently, both sertindole and levacetylmethadol were shown to prolong QTc interval during clinical trials. However, a great reliance is being placed on the ability of clinical trials – both in healthy volunteers given high single doses or multiple doses over very short periods during Phase I or in patients receiving 'normal' doses during Phase II/III – to uncover this risk. The crucial question from a regulatory perspective is how efficient and reliable these clinical trials are in achieving this objective, given the patient population enrolled, background noise arising from spontaneous intraindividual variability in QTc interval and the relatively low frequency of the clinically significant drug-induced cardiac effect [15]. The present efficacy-orientated approach is primarily responsible for failure of clinical trials to detect the risks of TdP. The numbers of patients exposed are not large enough nor are all the patient subgroups likely to receive the drug during its uncontrolled clinical use (and in fact at a much greater risk) represented in these preapproval clinical trials. These include those with predisposing diseases or those receiving drugs with a potential for pharmacokinetic or pharmacodynamic interactions. Thus, the scope for detecting drug-drug or drug–disease interactions in clinical trials is also very limited. And yet, the experience has shown that these are among the most important risk factors! Equally importantly, it is now recognized that the risk can vary from day to day depending on intercurrent event or intervention. The frequency of TdP or prolongation of the QTc interval to a proarrhythmic threshold (500 ms) varies with the class of drugs. Not unexpectedly, it is the highest with class III antiarrhythmic drugs. For noncardiac drugs, the frequency is unknown and can vary from approximately 1 in 100 (e.g. halofantrine) to 1 in 50 000 (e.g. terfenadine), depending on clinical circumstances. Overall, however, the frequency of this effect with noncardiac drugs is difficult to estimate. This is hardly surprising since the diagnosis of this particular toxicity requires an ECG monitoring facility which is either not available in general practice or when available in a local hospital, not utilized appropriately. Since TdP can be transient, its diagnosis in a patient presenting with symptoms suggestive of TdP, such as dizziness or syncope, requires immediate access to a cardiac rhythm recording facility. Even in asymptomatic patients, despite the requirements included in prescribing information, there is a general lack of appropriate patient monitoring by ECG. More importantly, however, the effect is often not recognized as iatrogenic and it is grossly under-reported (reporting rate is of the order of 10–20%) even when recognized as drug-induced. This was well exemplified by the events preceding the withdrawal of terodiline [16]. In all likelihood, the frequency of TdP or QTc interval >500 ms is relatively low (<0.1%) and below that which can be confidently detected by the size of the clinical trials database that is usually included in the regulatory submissions. The frequency is sufficiently low that the risk has usually been uncovered hitherto only through spontaneous reports during the postmarketing use of the drugs concerned. Although low, it is nonetheless unacceptable given the nature of the disease under treatment in many cases and the potential for a fatal outcome – that is, an adverse risk/benefit ratio. Halofantrine and arsenic trioxide best illustrate the careful need to balance the potential risk against the potential benefits. Trials conducted during the clinical development of a drug typically include 1500–3000 highly selected patients showing relatively little pharmacokinetic or pharmacodynamic variability. These are unlikely to identify the potential of a drug to induce TdP. A database of 1500 patients will barely detect an event which occurs at the rate of 1 in 1000, and almost certainly would miss one that occurs with a frequency of 1 in 5000 or less (α error of 0.05 and β error of 0.05). Long-term safety studies do not include adequate ECG monitoring at peak plasma concentrations of the drug or its metabolites. If the background incidence of an adverse event (e.g. TdP or QTc interval prolongation to proarrhythmic levels) to be detected is of the order of 1 in 1000 and the incidence of the same event to be detected, when drug-induced, is 1 in 1000, the number of patients required in the safety database would have to approach approximately 20 000. Clearly, it is impractical, and indeed undesirable, in the case of a highly novel or effective medicine, to have to complete such a large clinical trial programme (in terms of number of patients and/or the duration of exposure) before an application for a marketing authorization is filed. Thus, to assess the clinical risk of proarrhythmias, the regulatory agencies must rely upon the surrogate marker, namely QTc prolongation provided it is adequately investigated and quantified during drug development. The principles of development include testing a drug at more than its intended therapeutic dose to define a potential dose–response relationship and to also do so in the presence of its metabolic inhibitors, another method of stressing the system to define any potential effects of the drug on cardiac repolarization. A number of drugs such as terfenadine, astemizole, pimozide, cisapride and levacetylmethodol have had their potential to prolong the QTc interval and induce TdP uncovered as a result of drug–drug interactions [17–24]. These five drugs (and remarkably, many others with a potential to prolong the QTc interval) are metabolized by CYP3A4. The activity of this enzyme is also highly susceptible to liver disease. Not surprisingly, TdP in association with the clinical use of these drugs has been observed most frequently following their concurrent use with inhibitors of CYP3A4 such as azole antifungals and macrolide antibiotics [25, 26]. Other risk factors are liver disease (e.g. with terfenadine) and diabetes (e.g. with cisapride). Pharmacological studies of terfenadine, astemizole and cisapride best illustrate the role of metabolites. For terfenadine, its carboxylic acid metabolite, fexofenadine, is active as an antihistamine but is devoid of the IKr blocking property inherrent in the parent compound [27, 28]. Fexofenadine has now been developed for clinical use and is already on the market. This contrasts with the two metabolites of astemizole, namely desmethylastemizole and norastemizole. All of the three astemizole-related moieties are active as antihistamines, but the potential to prolong the QTc interval is predominantly present in astemizole and desmethylastemizole [29]. Indeed, the latter metabolite is slightly more potent in terms of cardiotoxicity and has a much longer elimination half-life compared with astemizole. At steady state following therapeutic doses, the plasma concentration of this major metabolite can be 30-fold higher than that of astemizole. In one patient with astemizole-induced TdP, concentrations were 7.7–17.3 ng ml−1 for desmethylastemizole and <0.5 ng ml−1 for astemizole [30]. Arguably, the proarrhythmic activity of astemizole during its clinical use probably derives largely from the presence of this metabolite in circulation. Norcisapride, the main metabolite of cisapride, has been shown to have a much lower proarrhythmic potential, if at all, than the parent drug [31]. Thus, as with fexofenadine, norastemizole is currently being developed clinically to replace astemizole and similarly, norcisapride to replace cisapride. Since prolongation of QTc interval is a concentration-dependent type A adverse reaction, its frequency can be greatly reduced by an appropriate dosing regimen of the drug concerned. Overdose with astemizole or terfenadine is often associated with cardiac arrhythmias [32, 33]. Astemizole was originally approved at a 10 mg daily dose, but it has a long half-life, requiring many days before steady state is achieved. Given that desmethylastemizole with its cardiotoxic potential has a much longer half-life than astemizole, the perils of recommending a loading dose of astemizole soon became evident. A recommendation to administer astemizole at a 30 mg daily loading dose for 1 week followed by 10 mg daily had to be re-revised to remove the loading dose recommendation following reports of cardiac arrhythmias [34]. Pimozide is another drug which has a half-life of approximately 55 hours in most individuals. This is hightly variable, being as long as 150 hours in some patients even in the absence of any inhibitors of its metabolism. It was introduced originally at a starting dose of 2–4 mg daily with a slow upward titration to a maximum daily dose of 10 mg. Subsequently, the starting dose was increased to 20 mg daily, the slow titration schedule was removed and the maximum daily dose was increased to 60 mg. Trials investigating the use of pimozide in schizophrenia in the USA had to be suspended in 1981 following the sudden deaths of two patients during acute titration of pimozide to 70–80 mg daily doses [35]. Following reports of QTc interval prolongation and TdP, the dosing schedule was re-amended to recommend an initial starting dose of 2 mg daily with a very shallow dose titration to a maximum daily dose of 16–20 mg. In the USA, pimozide is not approved for use in schizophrenia. Stereoselectivity in the pharmacological activity of a number of drugs acting at cardiac pharmacological targets is well known. For example, usually only one of the enantiomers of β-adrenoceptor blockers and dihydropyridine calcium channel blockers is pharmacologically active – either exclusively or dominantly. Stereoselectivity in activity at potassium channels has also been described for the enantiomers of some drugs. Examples include (+)-(R)-bupivacaine [36, 37] and (+)-(R)-halofantrine [38, 39]. The proarrhythmic activity of terodiline has been shown to reside in (+)-(R)-terodiline [40]. This is not surprising since it is structurally closely related to prenylamine whose proarrhythmic activity resides in its (+)-(S)-isomer [41]. Indeed, terodiline was marketed as an antianginal drug as long ago as 1965 before it was re-developed in mid-1980s for urinary incontinence following the observation of frequent and severe urinary retention associated with its cardiovascular use [16]. Although there is no information on its other isomers, (−)-(4S,6S)-acetylmethadol (levoacetylmethadol) has now been reported to be highly torsadogenic [42]. There is now an increasing trend to 'chiral switches' –the development of single enantiomers of previously marketed racemic drugs. This strategy is not without unforeseen potential risks. In view of its shorter half-life, the clinical availability of (R)-fluoxetine might represent a great advantage for clinical use of the drug in individuals in whom a greater dosing flexibility is required, e.g. in the elderly. This enantiomer may also be less prone to inhibit CYP2D6 compared with (S)-fluoxetine, which may also prove to be an advantage in the elderly who are likely to be receiving other CYP2D6 substrates. However, results from early clinical trials aimed at developing (R)-fluoxetine for clinical use suggest that the risk/benefit ratio of this enantiomer may warrant careful re-evaluation. Its use in about 2000 patients raised concerns over its potential to prolong the QTc interval at the highest dose administered. Indeed, this unexpected finding led to the termination of clinical development of this enantiomer [43]. In the context of QTc interval prolongation by drugs, pharmacogenetic influences can be significant at both pharmacokinetic and pharmacodynamic levels. At a pharmacokinetic level, the metabolism of a number of QTc prolonging drugs, especially the neuroleptics, antidepressants and cardiovascular agents, is predominantly under the control of CYP2D6, a major drug metabolizing enzyme that is polymorphically expressed in the population. These include sertindole [44], thioridazine [45], risperidone [46], indoramin [47], nortriptyline [48] and terikalant [49]. The QTc interval prolongation following the administration of terikalant has been shown to correlate with CYP2D6 metabolic capacity [49]. In addition, it appears that metabolism of terodiline and prenylamine may also be controlled by CYP2D6 [16]. The significance of this polymorphic metabolism lies in the fact that extensive metabolizers can be converted into impaired or poor metabolizers by the presence of liver disease or during concurrent administration of drugs that inhibit drug metabolizing enzymes (most frequently and vividly observed with CYP3A4). Arising from its CYP2D6-mediated metabolism, thioridazine is now contraindicated in patients known to have decreased levels of CYP2D6. At a pharmacodynamic level, mutations of potassium channels, resulting in diminished repolarization reserve, are common [1, 50] and these result in an increased susceptibility of the patient to proarrhythmias. Although congenital prolongation of QT interval was thought at one time to be a diagnostic requirement for the presence of these mutations, there is now incontestable evidence that these mutations may be clinically silent, and many of the affected individuals have a normal ECG phenotype [51, 52] but are nevertheless at an increased torsadogenic risk. Female gender is also at a greater risk [53] which is further heightened during menstrual flow [54]. There is a wider appreciation now of other nongenetic clinical conditions with increased pharmacodynamic susceptibility to proarrhythmic effect. QTc interval prolongation (and possibly increased QT dispersion) are associated with, and have been identified as risk factor(s) for malignant ventricular tachyarrhythmias in a variety of diseases. These include sudden deaths (usually labelled as sudden unexplained cardiac deaths) and a number of cardiovascular as well as noncardiovascular 'natural' diseases – for example, cardiomyopathy [55–57], cardiac failure [4, 58], myocardial infarction [59], sudden infant death syndrome [60], diabetic autonomic neuropathy [61–63], hypoglycaemia [64], cirrhosis [65] and a number of other conditions associated with autonomic failure [66, 67]. Cardiac failure is typically associated with down-regulation of potassium channels [68] and the concurrent presence of this cardiac disease obscures, or is often used to reject, the iatrogenic origin of proarrhythmias in patients receiving QT prolonging drugs. It is interesting to note that despite urinary incontinence, 27 of the 69 patients who experienced terodiline-induced proarrhythmias were receiving diuretics and 33 were in receipt of other cardioactive medications [16]. Clearly, the population at risk is much larger than had hitherto been recognized (only patients with cardiac disease). Factors contributing to this are increased longevity, frequent polypharmacy with risks of interactions and comorbidity. It is interesting to note that of the 2194 cases in the FDA database [8], 92.8% were reported between 1989 and 1998 in contrast to only 7.2% between 1969 and 1988. Increased publicity and clinical awareness of the problem cannot by themselves account for this dramatic rise in reporting. Cisapride represents an example of a unique drug with a target population that may already be at a greater risk of developing QTc interval prolongation and TdP. This risk was compounded by heavy use of contraindicated drugs despite regulatory warnings [11]. Cisapride is a gastric prokinetic drug approved in the UK in 1988 and in the USA in 1993. The maximum daily dose was 20–40 mg in the UK and 80 mg in the USA, in divided doses. Cisapride was indicated for the relief of symptoms of impaired gastric motility secondary to disturbed and delayed gastric emptying associated with diabetes, systemic sclerosis and autonomic neuropathy. As at 31 December 1999, the FDA database had included 341 reports of arrhythmias (of which 80 had a fatal outcome) associated with cisapride. A further 23 deaths were reported in the first 3 months of 2000, and in March 2000 severe limitation in its use in the US was announced. It is now available only for specific clinical eligibility criteria and for a limited-access protocol. The routine clinical use of cisapride in other markets was also discontinued or severely restricted. In view of the pharmacodynamic susceptibility of patients with (diabetic) autonomic neuropathy, it is not surprising that among the 159 cases of QTc prolongation or TdP associated with cisapride reported to the Uppsala Pharmacovigilance Centre as of 1999, about half reported no interacting medication, and by May 2000 six of the 20 deaths associated with cisapride occurred at doses of 40 mg or less in absence of known interactions [69]. Of course, the possibility of concurrent presence of silent mutations of potassium channels, having contributed either exclusively or partly to the risk, in these patients cannot be ruled out since diabetes itself is known to be associated with mutations of potassium channels [70]. The 'unexpected' association of this potentially fatal cardiotoxic effect with drugs of such diverse pharmacotherapeutic classes
Referência(s)