| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
FORUM |
From the Daiichi Medical Research, London, United Kingdom (Dr Darpo); the Department of Cardiology, Karolinska Hospital, Stockholm, Sweden (Dr Darpo); the Medical Sciences, Institut de Recherches Internationales SERVIER, Paris, France (Dr Nebout); Cardiovascular Research, AstraZeneca LP, Wilmington, Delaware (Dr Sager); and the University of Medicine and Dentistry of New Jersey, Newark, New Jersey (Dr Sager).
Address for reprints: Borje Darpo, MD, PhD, Daiichi Medical Research, 76 Shoe Lane, London EC4A 3JB United Kingdom; e-mail: borje.darpo{at}dmr.daiichius.com.
 |
ABSTRACT |
|---|
 TOP ABSTRACT THE ICH PROCESSTHE E14 DOCUMENTCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
|---|
Key Words: QT prolongation • ICH E14 • thorough QT study • ECG methodology
The Points to Consider document emphasized the need for nonclinical and clinical assessment of effects on cardiac repolarization and provided guidance as to how this could be achieved during drug development. In the view of some major regulatory agencies, in particular the Food and Drug Administration (FDA), these measures have not, however, been able to provide sufficient protection against the approval of new drugs that can trigger proarrhythmias during extreme conditions.7 The list of alleged compounds includes most therapeutic areas,7,8 and today TdP is the second most common reason for withdrawal of drugs from the market.9,10 QT prolongation has also resulted in a large number of drugs having precautionary statements in the label, among others moxifloxacin, vardenafil, alfuzosin, and ziprasidone. The incidence of drug-induced TdP is not well known, but estimates range from a few percentage with class III antiarrhythmics to a few cases in 100 000 patients with noncardiovascular drugs.5,8,11 The TdP incidence with nonantiarrhythmics may seem so low as to not cause significant concern, but it may result in mortality in patients being treated for benign conditions (eg, allergic rhinitis) and must obviously be balanced against the perceived benefit for the patients.
A need has therefore emerged for additional regulatory guidelines. Although the importance of the topic may seem limited and of concern mostly for regulators and the pharmaceutical industry, the new guidelines will have a significant impact on drug development and basic research regarding drug-induced proarrhythmias. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) E14 document, The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs,12 reached regulatory endorsement (step 4) in May 2005. The document is now in the process of regional implementation and was, as an example, endorsed by the Committee for Medicinal Products for Human Use in Europe on November 1, 2005. The measures proposed in this document will raise the investigational standards for clinical studies assessing QT effects and should enable an improved understanding of the relationship between effects on cardiac repolarization studied with nonclinical assays and QT prolongation in humans. Paired with intensified research on nonclinical proarrhythmic models and improvements in pharmacoepidemiologic research, these measures may eventually lead to the identification of better biomarkers than the QT interval for drug-induced proarrhythmic risk in patients. This topic is important because it is well appreciated that some drugs such as sodium pentobarbital, quetiapine, and amiodarone may cause QT prolongation with no or only a very small risk of TdP because of the inhibition of 2 or more ion channels. Amiodarone, as one example, has beta-blocking properties and also blocks sodium, potassium, and calcium channels in the heart. It clearly prolongs the QT interval, but unlike other class III antiarrhythmics, it has only a small effect on the cells of the midmyocardial layer (the M cells), thereby decreasing the transmural dispersion of repolarization and the proarrhythmic propensity.13
|
THE ICH PROCESS |
|---|
|
TOPABSTRACTTHE ICH PROCESSTHE E14 DOCUMENTCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
|---|
When consensus has been reached within the EWG and all parties on the ICH Steering Committee have endorsed a draft for public comments, the document achieves step 2, which indicates the formal start of regulatory actions. At this point, the document is published on the ICH Web site (www.ich.org) and elsewhere, and comments are solicited during a 6-month period (step 3). These comments are considered by the EWG, the document is accordingly revised, and when consensus is achieved, step 4 and endorsement of the final document by the ICH regulators is reached. During step 5, the guidance is implemented in all regions.
|
THE E14 DOCUMENT |
|---|
|
TOPABSTRACTTHE ICH PROCESSTHE E14 DOCUMENTCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
|---|
The Value of Nonclinical Testing
The ICH S7B document describes a nonclinical testing strategy to assess the propensity for new chemical entities to alter cardiac ventricular repolarization. This document also reached step 4 in May 2005 and should be regarded in conjunction with E14. The S7B advises that in vitro evaluation for effects on ionic currents (as measured in isolated cardiac myocytes, cultured cardiac cell lines, or heterologous expression systems for cloned human ion channels) and in vivo studies in dogs, for example, should be used to nonclinically assess a drug's QT-prolonging propensity. Follow-up assays, such as repolarization assays on canine Purkinje fiber or guinea pig papillary muscle, are recommended in ambiguous cases. Nonclinical assays are generally regarded as valuable and the S7B guidance (section 2.4) states, "Conduct of S7B nonclinical studies assessing the risk for delayed ventricular repolarization and QT interval prolongation prior to first administration in humans should be considered."14(p10) These assays will likely be required before first-dose-in-man studies in Europe and Japan, where regulators place larger emphasis on these assays and believe they are able to obviate the need for a clinical thorough QT study (see below), when the results are clearly negative. The FDA, on the other hand, believes that nonclinical assays are insufficiently characterized in regard to false negatives and wants to see more data on their predictive value. Consequently, the FDA will require a thorough clinical evaluation in almost all cases.
The Thorough QT Study
The E14 document recommends that almost all drugs should undergo careful clinical testing in a thorough QT study. The underlying concept is that a study using sufficiently high doses of a drug in healthy volunteers and designed to detect small QTc changes (in the vicinity of 5 milliseconds) will disclose any QT effect that may be seen in patients, recognizing that this latter group is more prone to develop proarrhythmias. The thorough QT study can therefore be performed in healthy volunteers whenever feasible. This concept remains to be proven, but evidence supports that for all drugs that have been associated with TdP, it has been possible to show a QT effect in carefully designed studies in healthy volunteers.15-19 Certain drugs, such as dopamine agonists, neuroleptics, and chemotherapeutics, cannot be readily tested in healthy volunteers, based on safety and tolerability issues. In such cases, the thorough QT study should be conducted in patients. When a thorough QT study is not feasible for other reasons, which may be the case in certain therapeutic areas such as oncology, alternative approaches should be sought, such as expanding the number and timings of electrocardiogram (ECG) recordings in other clinical studies in patients.
Timing
The thorough QT study requires sufficient knowledge of the exposure expected to be observed in patients with impaired clearance of the drug and should therefore not be performed before this expected exposure has been well characterized. This approach does not preclude careful QT monitoring in first-dose-in-man and maximum-tolerable-dose studies, as unparalleled exposure levels sometimes are achieved in these studies and useful data regarding the effect, or lack thereof, on the QT interval thereby can be obtained. The data collected in these early clinical pharmacology studies can provide important information regarding the effect size of a QT effect and permit accurate powering of the thorough QT study. Many sponsors are looking into QT monitoring during early development as a replacement for the thorough QT study, and the E14 document recognizes that alternative methodologies are under active investigation. These early studies often use parallel groups of subjects and do not typically include a positive control, which constitute limitations.
The timing of the thorough QT study within a clinical development program will also be influenced by various other factors, including whether the drug is targeted for a benign medical condition for which other effective therapies exist (in which case performing the study as early as feasible may be important because even a mildly positive study likely will result in program termination) or for the treatment of a life-threatening disease (in which case performing the study early may not be critical). An ambiguous nonclinical signal, which in itself may not cause project termination, could also justify the early conduct of the thorough QT study to quickly reach a decision on further development.
Design Consideration
A crossover or parallel design can be used, and two potential advantages with crossover design are identified: (1) smaller number of study subjects because of lower variability within subject than between subjects20 and (2) facilitation of heart rate correction approaches based on individual subject data. In some cases, parallel group studies may be needed because of long elimination half-life of the drug or pronounced carryover effects due to irreversible receptor binding or long-lived active metabolites. The study should be placebo controlled, randomized, and appropriately blinded. As the actual measurements of the ECG intervals must be done blindly, there may be less of a need for careful blinding of treatment, which often poses separate, logistical problems (eg, different tablet size or taste). The document asks for a baseline period but does not specify how this baseline period should be obtained: one 24-hour baseline day before the first treatment period, the same before each treatment period, or just a few ECGs before each period (eg, 3 recordings 5-30 minutes apart). All these methodologies have been used by sponsors, and the collection of multiple ECGs before dosing in each period is the most common approach when a crossover design is used. It has also been argued that the placebo period as such would sufficiently represent the baseline period. This issue is an area of on-going discussion, and more data are needed to establish the relative merits of each approach20 (see also Categorical Analysis).
Positive Controls
One of the most interesting points and the cause of considerable debate has been the requirement to include a positive control that "should be well-characterized and consistently produce an effect on the QT/QTc interval that is around the threshold of regulatory concern (5 ms)."12(p9) The objective of including a positive control is to validate the assay sensitivity; that is, the study should be powered and conducted to allow demonstration of a statistically significant effect in the 5-millisecond range. If the study fails to demonstrate an effect of this size induced by the positive control, there would essentially be no confidence in the lack of effect by the drug under investigation—the distinction between true absence of an effect from low sensitivity of the study to demonstrate a small effect is not possible in this event. The inclusion of the positive control in the thorough QT study does not, however, guarantee a valid design—the timing of ECG recordings must capture the maximum plasma concentration (Cmax) of both the positive control and the investigational drug.
A recent example on the use of a positive control was given at the FDA's Cardio-Renal Advisory Board meeting in May 2003, at which data from studies with alfuzocin, an alpha-1 blocker with intended use as treatment of benign prostatic hyperplasia, and vardenafil, a phosphodiesterase-5 inhibitor for treatment of sexual dysfunction, were presented.21 In both studies, moxifloxacin, a fluoroquinolone known to have a small effect on the QT interval,16,22,23 was used as a positive control, and the effect sizes observed with different methods could be compared. Table I shows the effect of moxifloxacin in the US New Drug Application (NDA) and in 4 clinical studies. The effect described in the NDA is a composite from all studies using different doses and different timings of the ECGs, and the effect size is therefore clearly lower than in studies assessing the effect at Cmax of the drug.
|
A clear advantage with using the same positive control in different studies is that effect sizes can be compared across methods24,25 and across studies. Nonpharmacologic approaches, such as autonomic maneuvers,26-29 exercise under tightly controlled conditions,30 or even food ingestion31 can also be used as positive controls. In the study by Frederiks et al,28 static hand grip prolonged the Fridericia-corrected QT value (QTcF) from 413 milliseconds at baseline (at 65 beats per minute [bpm]) to 422 milliseconds (72 bpm), whereas leg lowering decreased the same interval to 406 milliseconds (72 bpm). It may, however, be difficult to design such maneuvers in a way that consistently produces similar effect sizes across different studies and with sufficiently small variability, which may limit their usefulness.
In most cases, thorough QT studies will be performed in a controlled setting, such as in a phase I unit, with in-house healthy volunteers, using modern telemetry and safety surveillance. The proarrhythmic risk induced by agents that only mildly prolong the QT interval is extremely low in healthy volunteers and will therefore be ethically acceptable in most regions. There are, however, exceptions, and in Japan, for example, it can be anticipated that nonpharmacologic positive controls might be used more frequently.
Doses and Duration of Dosing
Sufficiently high plasma concentrations should be achieved "including exploration of concentrations that are higher than those achieved following the anticipated therapeutic doses."12(p8) When estimating the doses for the study, it is important not only to look at mean exposure in patients but also to take variability into account. High exposure can be achieved through the use of high doses or through metabolic inhibition such as with concomitant administration of a drug that decreases the clearance of the drug under investigation. As these 2 approaches result in clearly different plasma levels of the metabolite that is dependent on the inhibited pathway (Figure 1), it seems prudent to recommend the use of metabolic inhibition only when the electrophysiologic effects of the metabolites are nonclinically characterized.
|
The E14 document does not specifically prescribe single-dose studies or dosing to steady state, but states, "In general, the duration of dosing or dosing regimen should be sufficient to characterize the effects of the drug and its active metabolites at relevant concentrations."12(p9) When dosing to steady state results in exposure and/or Cmax to levels that cannot be achieved with single dosing, multiple dosing would be the preferred design. Dosing to steady state of the parent compound may also increase the ability to demonstrate any effects on the QT interval caused by yet unknown metabolites for which single dosing may not result in sufficiently high plasma levels. Besides these considerations, there are obvious advantages of the single-dose design for feasibility and cost of the study.
Collection and Measurements of Electrocardiographic Data
The QT/QTc interval is subject to intrinsic and measurement-related variability, which is essential to address in the study. Electrocardiograms should be recorded at multiple time points after dosing, always including time points capturing the anticipated Cmax. One way of reducing the observed QT interval variability is to average the ECG intervals from more than 1 recording at each nominal time point (replicate recordings). The largest reduction in variability is seen when increasing the number of recordings from 1 to 3 (2 minutes apart), and higher numbers of replicates (up to 10) only marginally add to this reduction.20
Twelve-lead ECG recordings at discrete time points are still the recommended option, but other techniques may be used, such as Holter-based techniques, as long as validation is provided. The same applies to the actual technique of measuring the ECG intervals—having a few skilled readers, whether computer assisted (semiautomatic) or not (fully manual), operating from a central ECG laboratory is generally recommended. Other techniques, including fully automated,32-34 will emerge and can be anticipated to replace manual techniques, once validated.
Profound T wave morphological changes can be seen with potent potassium channel blockers, and the severity of these changes has been shown to be more pronounced in patients who subsequently develop TdP.35 Whether T wave classification in healthy volunteers with a drug-induced mild QT prolongation is of any predictive value for subsequent proarrhythmic events in patients is unknown, and there are no data to support this assumption. Despite these potential limitations, the E14 document asks for an assessment of T wave morphologic changes. A standardized approach to assessing T wave morphology changes across ECG laboratories, and sponsors has yet to be developed and agreed on; we propose the following:
Which algorithm, if any, that should be used for heart rate correction is probably one of the most intensely debated issues among scientists in this field.36-38 It is widely acknowledged that the Bazett algorithm (QTcB)39 overcorrects the QT interval at elevated heart rates. Despite this finding, on which all involved parties agreed, the QTcB, along with uncorrected QT and QTcF, should be reported mainly to allow comparison with historical data on file in previous submissions to regulators. In most cases, the primary choice will be correction algorithms other than QTcB, such as QTcF or other population-based, within-subject or within-study derived algorithms, and the primary methodology should be prespecified in the protocol. An interesting alternative can be the Holter bin approach,40,41 in which the use of a heart rate correction algorithm is avoided. QRS complexes with preceding RR interval within predefined limits (eg, 680 to 690 milliseconds) are pooled, and the QT interval measurement is performed on the signal-averaged pattern. Hereby, an effect on the QT interval can be detected throughout a range of heart rates. It should be noted that because 2 to 4 hours of ECG recording is required to yield a sufficient number of QRS complexes in each bin, any short-lasting drug-induced QT effect will be "averaged-out" during this time period. The Holter bin approach may therefore yield a somewhat lower value than the time-matched approach, in which a limited number of ECGs are recorded at peak plasma concentration.21
Analysis and Definition of a Negative Thorough QT Study Result
The analysis of QT data should include both central tendency (eg, mean effects) and categorical analysis. The definition of a negative thorough QT study result is based on changes in central tendency.
|
The number of subjects, which will allow the study to meet the stringent criteria for assay sensitivity (see Positive Controls), depends on the effect size and on the variability of the QT interval. The QT variability is lower in healthy volunteers than in patients, and a residual standard deviation between 10 and 15 milliseconds is often seen in carefully controlled studies.42 Measures that decrease this variability will have substantial impact on the required sample size (Table II, note that these sample sizes assume 1 ECG test only, which is not entirely correct in a through QT study, in which repeated tests are performed and the maximum change from baseline will be used; the numbers shown in the table should however provide reasonable estimates of the sample sizes).
|
Categorical analysis. Results should also be displayed as the proportion of ECG recordings (or subjects), which exceeds certain absolute values (QTc >450 milliseconds, >480 milliseconds, >500 milliseconds) and increases from baseline (QTc 
30 milliseconds, 60 milliseconds). It is recognized that the thorough QT/QTc study is not adequately powered to provide statistically significant results for small increases of categorical outliers. Some regulators regard this analysis, however, as a useful exploratory tool to scrutinize any potential effects on cardiac repolarization in susceptible persons, even though the relative value is probably larger in studies in patients. One way to achieve some degree of protection against random effects is to include the placebo arm in the analysis. To enable the increase-from-baseline analysis, a baseline assessment (eg, during 1 hour before dosing in each arm) has to be included.
Whether there are drugs that cause an effect only in categorical response (ie, exaggerated effect in susceptible patients), without a corresponding mean effect in healthy volunteers, using sufficiently high exposure, is an area of debate. To our best knowledge, all drugs that have been clearly associated with TdP show an effect on the mean QTc interval, when carefully studied, and we are not aware of any drug that has caused marked categorical changes without affecting the central tendency.16-19,30
The Thorough QT/QTc Study's Impact on the Clinical Program
The outcome of the thorough QT/QTc study has a major impact on the level of ECG monitoring in subsequent trials. For compounds with a negative thorough QT study, "the collection of baseline and periodic on-therapy ECGs in accordance with the current investigational practices in each therapeutic field is almost always sufficient evaluation."12(p9) In most cases, this means that additional data on ECG intervals, especially QT intervals, are not required, except in cases when these intervals are reported as part of an adverse event (such as treatment emergent AV block I with PR 240 milliseconds; bundle-branch block with QRS 140 milliseconds; marked QT prolongation with QT 540 milliseconds). It should be noted that there are clear differences in opinion among regulators regarding the predictive value of the S7B nonclinical studies and the E14 thorough QT study. The FDA would, in most cases, accept that clinical data override nonclinical data and would regard a compound as devoid of proarrhythmic propensity if negative in the thorough QT study, regardless of the S7B nonclinical battery. This is not the case among European regulators, and this difference was met in the document by acknowledging that there may be "very unusual cases,"12(p7) in which nonclinical assays are strongly positive and the thorough QT study results are negative. If this discrepancy cannot be explained by other data and if the drug belongs to a pharmacologic class of concern, an expanded ECG assessment should be performed during late-stage development (similar to the case for drugs with a positive thorough QT study result, see below).
A positive thorough QT study result will, on the other hand, require that the QT effect be further evaluated in the targeted patient population. This evaluation could be achieved by the collection of QT interval data at baseline and on therapy with a limited number of ECG recordings in "substantial numbers of patients in late phase clinical trials."12(p10) It would be important to ensure that on-therapy ECGs were recorded at the anticipated time of peak drug effect. The objective is to fully describe the QT effect in patients with emphasis on dose-related and concentration-related responses. Patients with risk factors for TdP (such as female gender or cardiac disease) should be included in these analyses, which would not only focus on mean effects but also place an emphasis on outlier values in individual patients.
Once approved, contraindication for certain patient groups may apply, and the effect on the QT interval needs to be clearly described in the label, as well as in precautionary advisories for the prescribing physician and for patients.
|
CONCLUSION |
|---|
|
TOPABSTRACTTHE ICH PROCESSTHE E14 DOCUMENTCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
|---|
|
ACKNOWLEDGEMENTS |
|---|
|
TOPABSTRACTTHE ICH PROCESSTHE E14 DOCUMENTCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
|---|
|
REFERENCES |
|---|
|
TOPABSTRACTTHE ICH PROCESSTHE E14 DOCUMENTCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
|---|
1. Committee for Proprietary Medicinal Products. Points to Consider: The Assessment of the Potential for QT Interval Prolongation by Non-Cardiovascular Medicinal Products. London, United Kingdom: Committee for Proprietary Medicinal Products; December 17, 1997.
2. Shah R. Withdrawal of terodiline: a tale of two toxicities. In: Mann RD, Andrews EB, eds. Pharmacovigilance. London, United Kingdom: John Wiley & Sons; 2002: 135-154.
3. Shah RR. The significance of QT interval in drug development. Br J Clin Pharmacol. 2002;54: 188-202.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
4. Pratt CM, Ruberg S, Morganroth J, et al. Dose-response relation between terfenadine (Seldane) and the QTc interval on the scalar electrocardiogram: distinguishing a drug effect from spontaneous variability. Am Heart J. 1996;131: 472-480.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
5. Wysowski DK, Bacsanyi J. Cisapride and fatal arrhythmia [letter]. N Eng J Med. 1996;335: 290-291.
6. Yap YG, Camm AJ. Arrhythmogenic mechanisms of non-sedating antihistamines. Clin Exp Allergy. 1999;29: 174-181.
7. Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart. 2003;89: 1363-1372.
8. Darpo B. Spectrum of drugs prolonging the QT interval and the incidence of torsades de pointes. Eur Heart J. 2001;3(suppl K): 70-80.
9. Shah RR. Drug-induced prolongation of the QT interval: why the regulatory concern? Fundam Clin Pharmacol. 2002;16: 119-124.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
10. Shah RR. Drug-induced prolongation of the QT interval: regulatory dilemmas and implications for approval and labelling of a new chemical entity. Fundam Clin Pharmacol. 2002;16: 147-156.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
11. Barbey JT, Lazzara R, Zipes DP. Spontaneous adverse event reports of serious ventricular arrhythmias, QT prolongation, syncope, and sudden death in patients treated with cisapride. J Cardiovasc Pharmacol Ther. 2002;7: 65-76.
12. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs: E14. Geneva, Switzerland: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use; 2005. Available at http://www.ich.org/LOB/media/MEDIA1476.pdf.
13. Antzelevitch C. Cellular, molecular and pharmacologic mechanisms underlying drug-induced cardiac arrhtyhmogenesis. In: Morganroth J, Gussak I, eds. Cardiac Safety of Noncardiac Drugs: Practical Guidelines for Clinical Research and Drug Development. Totowa, NJ: Humana Press.
14. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. The Non-Clinical Evaluation of The Potential For Delayed Ventricular Repolarization (Qt Interval Prolongation) by Human Pharmaceuticals: S7B. Geneva, Switzerland: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use; 2005. Available at http://www.ich.org/LOB/media/MEDIA2192.pdf.
15. Demolis JL, Charransol A, Funck-Brentano C, Jaillon P. Effects of a single oral dose of sparfloxacin on ventricular repolarization in healthy volunteers. Br J Clin Pharmacol. 1996;41: 499-503.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
16. Demolis JL, Kubitza D, Tenneze L, Funck-Brentano C. Effect of a single oral dose of moxifloxacin (400 mg and 800 mg) on ventricular repolarization in healthy subjects. Clin Pharmacol Ther. 2000;68: 658-666.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
17. Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR. Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequences. JAMA. 1993;269: 1513-1518.
18. Kivisto KT, Lilja JJ, Backman JT, Neuvonen PJ. Repeated consumption of grapefruit juice considerably increases plasma concentrations of cisapride. Clin Pharmacol Ther. 1999;66: 448-453.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
19. van Haarst AD, van't Klooster GA, van Gerven JM, et al. The influence of cisapride and clarithromycin on QT intervals in healthy volunteers. Clin Pharmacol Ther. 1998;64: 542-546.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
20. Agin M, Kazierad DJ, Abel R, et al. Assessing QT variability in healthy volunteers. In press.
21. US Food and Drug Administration. FDA review for Uroxatral (alfuzocin HCl tablets). May 29, 2003. Available at: http://www.fda.gov/ohrms/dockets/ac/03/briefing/3956B1_01_FDA-alfuzosin.pdf.
22. Noel GJ, Natarajan J, Chien S, Hunt TL, Goodman DB, Abels R. Effects of three fluoroquinolones on QT interval in healthy adults after single doses. Clin Pharmacol Ther. 2003;73: 292-303.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
23. White CM, Grant EM, Quintiliani R. Moxifloxacin does increase the corrected QT interval. Clin Infect Dis. 2001;33: 1441-1444.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
24. Azie NE, Adams G, Darpo B, et al. Comparing methods of measurement for detecting drug-induced changes in the QT interval: implications for thoroughly conducted ECG studies. Ann Noninvasive Electrocardiol. 2004;9: 166-174.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
25. Sarapa N, Morganroth J, Couderc JP, et al. Electrocardiographic identification of drug-induced QT prolongation: assessment by different recording and measurement methods. Ann Noninvasive Electrocardiol. 2004;9: 48-57.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
26. Cuomo S, De Caprio L, Di Palma A, et al. Influence of autonomic tone on QT interval duration. Cardiologia. 1997;42: 1071-1076.[Medline] [Order article via Infotrieve]
27. Diedrich A, Jordan J, Shannon JR, Robertson D, Biaggioni I. Modulation of QT interval during autonomic nervous system blockade in humans. Circulation. 2002;106: 2238-2243.
28. Frederiks J, Swenne CA, Kors JA, et al. Within-subject electrocardiographic differences at equal heart rates: role of the autonomic nervous system. Pflugers Arch. 2001;441: 717-724.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
29. Piccirillo G, Cacciafesta M, Lionetti M, et al. Influence of age, the autonomic nervous system and anxiety on QT-interval variability. Clin Sci (Lond). 2001;101: 429-438.
30. Demolis JL, Vacheron F, Cardus S, Funck-Brentano C. Effect of single and repeated oral doses of telithromycin on cardiac QT interval in healthy subjects. Clin Pharmacol Ther. 2003;73: 242-252.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
31. Nagy D, DeMeersman R, Gallagher D, et al. QTc interval (cardiac repolarization): lengthening after meals. Obes Res. 1997;5: 531-537.[Web of Science][Medline] [Order article via Infotrieve]
32. Darpo B, Agin M, Kazierad DJ, et al. Man versus machine: is there an optimal method for QT measurements in thorough QT studies? In press.
33. Dota C, Skallefell B, Edvardsson N, Fager G. Computer-based analysis of dynamic QT changes: toward high precision and individual rate correction. Ann Noninvasive Electrocardiol. 2002;7: 289-301.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
34. Dota CD, Edvardsson N, Schutzer KM, et al. Inter- and intraday variability in major electrocardiogram intervals and amplitudes in healthy men and women. Pacing Clin Electrophysiol. 2003;26: 361-366.[CrossRef][Medline] [Order article via Infotrieve]
35. Houltz B, Darpo B, Edvardsson N, et al. Electrocardiographic and clinical predictors of torsades de pointes induced by almokalant infusion in patients with chronic atrial fibrillation or flutter: a prospective study. Pacing Clin Electrophysiol. 1998;21: 1044-1057.[CrossRef][Medline] [Order article via Infotrieve]
36. Malik M, Camm AJ. Evaluation of drug-induced QT interval prolongation: implications for drug approval and labelling. Drug Saf. 2001;24: 323-351.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
37. Malik M. Problems of heart rate correction in the assessment of drug-induced QT interval prolongation. J Cardiovasc Electrophysiol. 2001;12: 412-420.
38. Malik M, Farbom P, Batchvarov V, Hnatkova K, Camm AJ. Relation between QT and RR intervals is highly individual among healthy subjects: implications for heart rate correction of the QT interval. Heart. 2002;87: 220-228.
39. Bazett HC. An analysis of time relations of electrocardiograms. Heart. 1920; 353-367.
40. Extramiana F, Maison-Blanche P, Cabanis MJ, Ortemann-Renon C, Beaufils P, Leenhardt A. Clinical assessment of drug-induced QT prolongation in association with heart rate changes. Clin Pharmacol Ther. 2005;77: 247-258.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
41. Malik M. Assessment of drug-induced QT prolongation: to bin or not to bin? Clin Pharmacol Ther. 2005;77: 241-246.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
42. Patterson S, Agin M, Anziano R, et al. Investigating drug-induced QT and QTc Prolongation in the clinic: a review of statistical design and analysis considerations. Report from pharmaceutical Research and Manufacturer of America QT statistics expert team. In press.
43. Hanrahan JP, Choo PW, Carlson W, Greineder D, Faich GA, Platt R. Terfenadine-associated ventricular arrhythmias and QTc interval prolongation: a retrospective cohort comparison with other antihistamines among members of a health maintenance organization. Ann Epidemiol. 1995;5: 201-209.[CrossRef][Medline] [Order article via Infotrieve]
44. Walker AM, Szneke P, Weatherby LB, et al. The risk of serious cardiac arrhythmias among cisapride users in the United Kingdom and Canada. Am J Med. 1999;107: 356-362.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  N. Sarapa, S. F. Francom, S. M. Azzam, P. K. Wickremasingha, and B. Tyl Detection of Clinically Significant QTc Prolongation in Phase I Studies in Healthy Participants: Comparison of 2 Semiautomated QT Measurement Methods J. Clin. Pharmacol., January 1, 2009; 49(1): 103 - 108. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Peeters, K. Janssen, T. N Kakuda, M. Scholler-Gyure, R. Lachaert, R. M. Hoetelmans, B. Woodfall, and G. De Smedt Etravirine Has No Effect on QT and Corrected QT Interval in HIV-Negative Volunteers Ann. Pharmacother., June 1, 2008; 42(6): 757 - 765. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Hutmacher, S. Chapel, M. A. Agin, J. C. Fleishaker, and R. L. Lalonde Performance Characteristics for Some Typical QT Study Designs Under the ICH E-14 Guidance J. Clin. Pharmacol., February 1, 2008; 48(2): 215 - 224. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Roden, P. Kannankeril, and D. Darbar On the relationship among QT interval, atrial fibrillation, and torsade de pointes Europace, September 1, 2007; 9(suppl_4): iv1 - iv3. [Full Text] [PDF]
|
|
|
|
|
|
B. Darpo Detection and reporting of drug-induced proarrhythmias: room for improvement Europace, September 1, 2007; 9(suppl_4): iv23 - iv36. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
