Population pharmacokinetics and pharmacodynamics of escitalopram in overdose and the effect of activated charcoal

AIMS

To describe the pharmacokinetics and pharmacodynamics (PKPD) of escitalopram in overdose and its effect on QT prolongation, including the effectiveness of single dose activated charcoal (SDAC).

METHODS

The data set included 78 escitalopram overdose events (median dose, 140 mg [10–560 mg]). SDAC was administered 1.0 to 2.6 h after 12 overdoses (15%). A fully Bayesian analysis was undertaken in WinBUGS 1.4.3, first for a population pharmacokinetic (PK) analysis followed by a PKPD analysis. The developed PKPD model was used to predict the probability of having an abnormal QT as a surrogate for torsade de pointes.

RESULTS

A one compartment model with first order input and first-order elimination described the PK data, including uncertainty in dose and a baseline concentration for patients taking escitalopram therapeutically. SDAC reduced the fraction absorbed by 31% and reduced the individual predicted area under the curve adjusted for dose (AUC_i/dose). The absolute QT interval was related to the observed heart rate with an estimated individual heart rate correction factor (α = 0.35). The heart rate corrected QT interval (QT_c) was linearly dependent on predicted escitalopram concentration [slope = 87 ms/(mg l^–1)], using a hypothetical effect-compartment (half-life of effect-delay, 1.0h). Administration of SDAC significantly reduced QT prolongation and was shown to reduce the risk of having an abnormal QT by approximately 35% for escitalopram doses above 200 mg.

CONCLUSIONS

There was a dose-related lengthening of the QT interval that lagged the increase in drug concentration. SDAC resulted in a moderate reduction in fraction of escitalopram absorbed and reduced the risk of the QT interval being abnormal.     

Citalopram overdose: Late presentation of torsades de pointes (TdP) with cardiac arrest

Introduction

Citalopram overdose may produce bradycardia, QT prolongation, and torsades de pointes (TdP). A cardiotoxic metabolite may be responsible for the delayed onset of cardiotoxicity. Although some authorities recommend a minimum of 24 hours of observation following citalopram overdose, a recent analysis suggested that dysrhythmias rarely occur beyond 13 hours post-ingestion. We present a case of citalopram overdose with a substantially delayed onset of cardiac toxicity.

Case Report

A 36-year-old woman complained of shakiness, numbness in the arms, and palpitations that began approximately 32 hours after ingesting 50 (20-mg) tablets of citalopram. Her initial vital signs were: blood pressure, 84/44 mmHg; pulse, 102–150/minute; respirations, 17/min; temperature, 99.3° F (37.3° C). Her initial ECG showed sinus rhythm with a prolonged corrected QT interval (572 msec) with paroxysmal, self-limited runs of wide-complex tachycardia that appeared multifocal in nature. Approximately 20 minutes after presentation, she experienced self-terminating TdP, with transient hypotension and loss of consciousness. Her serum citalopram concentration (33 hours post-ingestion) was 477 ng/mL (therapeutic: 40–110 ng/mL); desmethylcitalopram concentration was 123.2 ng/mL (therapeutic: 14–40 ng/mL). She was treated with magnesium and lidocaine, and her corrected QT interval remained abnormal for 24 hours after presentation.

Discussion

Citalopram overdose can produce life-threatening cardiac toxicity with a clinical onset that may be delayed beyond a routine observation period of 6 hours. Once the QT interval is prolonged, it seems prudent to prolong the observation period.     

Fluconazole- and levofloxacin-induced torsades de pointes in an intensive care unit patient.

Patients initiated on fluconazole and levofloxacin should be closely monitored for QTc-interval prolongation. While there have been published reports of fluconazole and levofloxacin causing QTc-interval prolongation when given alone, coadministration of these two agents may further increase this risk. This case describes an episode of TdP in which levofloxacin and fluconazole were likely significant factors. QT prolongation was present at baseline prior to drug initiation (QTc = 454-505 ms) and levofloxacin resulted in further prolongation (QTc = 480-536 ms). After two days of therapy with fluconazole, overlapping with levofloxacin, the patient had an episode of PMVT with syncope, and progressive QT prolongation was evident (QTc = 554 ms). Only mild hypokalemia (potassium concentration = 3.6 meq/L) was present, and not additional etiologies for TdP were identified. Levofloxacin and fluconazole were discontinued and no further PMVT was observed, but the QT interval did not return to normal until after an additional 11 days (QTc = 436 ms). As in many cases of TdP, multiple factors were involved. Renal failure, drug dosing, mild hypokalemia, and a baseline abnormal QT interval potentiated the role of levofloxacin and fluconazole in the development of TdP. We recommend that neither drug be used alone or in combination when there is baseline QT prolongation. We also recommend that concomitant use of these agents be avoided when possible. If combination therapy is required, caution is warranted, particularly in patients with risk factors for QT prolongation. Specific attention should be given to drug dosing, interactions, electrolytes, and ECG monitoring.     

Drug monitoring of a case of citalopram overdosage

Selective serotonin reuptake inhibitors are widely prescribed drugs without recognized cardiovascular risk. We report the case of a 54-year-old patient who developed QTc interval prolongation, followed by ventricular fibrillation episodes, 10 hours after admission to the ICU, in the setting of a citalopram overdose. Citalopram plasma values dropped from 5.88 to 0.34?mg/L at 9 days postadmission. The patient was treated by oral activated charcoal, and final outcome was favorable.     

Combined pharmacological block of I(Kr) and I(Ks) increases short-term QT interval variability and provokes torsades de pointes

BACKGROUND AND PURPOSE: Assessing the proarrhythmic potential of compounds during drug development is essential. However, reliable prediction of drug-induced torsades de pointes arrhythmia (TdP) remains elusive. Along with QT interval prolongation, assessment of the short-term variability of the QT interval (STV(QT)) may be a good predictor of TdP. We investigated the relative importance of I(Ks) and I(Kr) block in development of TdP together with correlations between QTc interval, QT interval variability and incidence of TdP. EXPERIMENTAL APPROACH: ECGs were recorded from conscious dogs and from anaesthetized rabbits given the I(Kr) blocker dofetilide (DOF), the I(Ks) blocker HMR-1556 (HMR) and their combination, intravenously. PQ, RR and QT intervals were measured and QTc and short-term variability of RR and QT intervals calculated. KEY RESULTS: DOF increased QTc interval by 20% in dogs and 8% in rabbits. HMR increased QTc in dogs by 12 and 1.9% in rabbits. Combination of DOF+HMR prolonged QTc by 33% in dogs, by 16% in rabbits. DOF or HMR given alone in dogs or HMR given alone in rabbits induced no TdP. Incidence of TdP increased after DOF+HMR combinations in dogs (63%) and following HMR+DOF (82%) and DOF+HMR combinations (71%) in rabbits. STV(QT) markedly increased only after administration of DOF+HMR combinations in both dogs and rabbits. CONCLUSION AND IMPLICATIONS: STV(QT) was markedly increased by combined pharmacological block of I(Kr) and I(Ks) and may be a better predictor of subsequent TdP development than the measurement of QTc interval prolongation.     

Effects of a single oral dose of sparfloxacin on ventricular repolarization in healthy volunteers

1 Sparfloxacin, a new fluoroquinolone, slightly increases the duration of the QT interval. Reverse rate-dependence of QT interval prolongation has been shown for many agents that are known to prolong QT interval duration, and QT prolongation at slow heart rates may be a risk factor for torsades de pointes.
2 A double-blind, randomized, placebo controlled, crossover study was performed in 15 healthy volunteers to determine the effects of single oral doses of sparfloxacin (200 and 400  mg) on the QT interval at various heart rates.
3 12-lead ECGs were recorded at rest and during exercise tests 5  h after sparfloxacin or placebo administration. QT intervals were calculated at predetermined RR intervals (1000, 800, 700, 600, 500 and 400 ms) after individual QT-RR curve fitting.
4 Sparfloxacin at both doses induced prolongation of the QT interval which was around 4% greater than placebo. No significant reverse rate-dependence of QT interval prolongation was observed.
5 Oral administration of sparfloxacin appears unlikely to be associated with marked QT interval prolongation.     

Drug monitoring of a case of citalopram overdosage

Selective serotonin reuptake inhibitors are widely prescribed drugs without recognized cardiovascular risk. We report the case of a 54-year-old patient who developed QTc interval prolongation, followed by ventricular fibrillation episodes, 10 hours after admission to the ICU, in the setting of a citalopram overdose. Citalopram plasma values dropped from 5.88 to 0.34?mg/L at 9 days postadmission. The patient was treated by oral activated charcoal, and final outcome was favorable.     

Assessing QT interval prolongation and its associated risks with antipsychotics

Several antipsychotics are associated with the ventricular tachycardia torsade de pointes (TdP), which may lead to sudden cardiac death (SCD), because of their inhibition of the cardiac delayed potassium rectifier channel. This inhibition extends the repolarization process of the ventricles of the heart, illustrated as a prolongation of the QT interval on a surface ECG. SCD in individuals receiving antipsychotics has an incidence of approximately 15 cases per 10,000 years of drug exposure but the exact association with TdP remains unknown because the diagnosis of TdP is uncertain. Most patients manifesting antipsychotic-associated TdP and subsequently SCD have well established risk factors for SCD, i.e. older age, female gender, hypokalaemia and cardiovascular disease. QT interval prolongation is the most widely used surrogate marker for assessing the risk of TdP but it is considered somewhat imprecise, partly because QT interval changes are subject to measurement error. In particular, drug-induced T-wave changes (e.g. flattening of the T-wave) may complicate the measurement of the QT interval. Furthermore, the QT interval depends on the heart rate and a corrected QT (QTc) interval is often used to compensate for this. Several correction formulas have been suggested, with Bazett's formula the most widely used. However, Bazett's formula overcorrects at a heart rate above 80 beats per minute and, therefore, Fridericia's formula is considered more appropriate to use in these cases. Several other surrogate markers for TdP have been developed but none of them is clinically implemented yet and QT interval prolongation is still considered the most valid surrogate marker. Although automated QT interval determination may offer some assistance, QT interval determination is best performed by a cardiologist skilled in its measurement. A QT interval >500?ms markedly increases the risk for TdP and SCD, and should lead to discontinuation of the offending drug and, if present, correction of underlying electrolyte disturbances, particularly serum potassium and magnesium derangements. Before prescribing antipsychotics that may increase the QTc interval, the clinician should ask about family and personal history of SCD, presyncope, syncope and cardiac arrhythmias, and recommend cardiology consultation if history is positive.     

Antipsychotic-related QTc prolongation,torsade de pointes and sudden death

Sudden unexpected deaths have been reported with antipsychotic use since the early 1960s. In some cases the antipsychotic may be unrelated to death, but in others it appears to be a causal factor. Antipsychotics can cause sudden death by several mechanisms, but particular interest has centred on torsade de pointes (TdP), a polymorphic ventricular arrhythmia that can progress to ventricular fibrillation and sudden death. The QTc interval is a heart rate-corrected value that represents the time between the onset of electrical depolarisation of the ventricles and the end of repolarisation. Prolongation of the QTc interval is a surrogate marker for the ability of a drug to cause TdP. In individual patients an absolute QTc interval of >500 msec or an increase of 60 msec from baseline is regarded as indicating an increased risk of TdP. However, TdP can occur with lower QTc values or changes. Concern about a relationship between QTc prolongation, TdP and sudden death applies to a wide range of drugs and has led to the withdrawal or restricted labelling of several. Among antipsychotics available in the UK, sertindole was voluntarily suspended, droperidol was withdrawn, and restricted labelling introduced for thioridazine and pimozide. The degree of QTc prolongation is dose dependent and varies between antipsychotics reflecting their different capacity to block cardiac ion channels. Significant prolongation is not a class effect. Among currently available agents, thioridazine and ziprasidone are associated with the greatest QTc prolongation. Virtually all drugs known to cause TdP block the rapidly activating component of the delayed rectifier potassium current (I(kr)). Arrhythmias are more likely to occur if drug-induced QTc prolongation coexists with other risk factors, such as individual susceptibility, presence of congenital long QT syndromes, heart failure, bradycardia, electrolyte imbalance, overdose of a QTc prolonging drug, female sex, restraint, old age, hepatic or renal impairment, and slow metaboliser status. Pharmacodynamic and pharmacokinetic interactions can also increase the risk of arrhythmias. Further research is needed to quantify the risk of sudden death with antipsychotics. The risk should be viewed in the context of the overall risks and benefits of antipsychotic treatment. It seems prudent, where possible, to select antipsychotics that are not associated with marked QTc prolongation. If use of a QTc-prolonging drug is warranted, then measures to reduce the risk should be adopted.     

Transmural Dispersion of Repolarization as a Preclinical Marker of Drug-induced Proarrhythmia

ABSTRACT:: Torsade de Pointes (TdP) proarrhythmia is a major complication of therapeutic drugs that block the delayed rectifier current. QT interval prolongation, the principal marker used to screen drugs for proarrhythmia, is both insensitive and nonspecific. Consequently, better screening methods are needed. Drug-induced transmural dispersion of repolarization (TDR) is mechanistically linked to TdP. Therefore, we hypothesized that drug-induced enhancement of TDR is more predictive of proarrhythmia than QT interval. High-resolution transmural optical action potential mapping was performed in canine wedge preparations (n = 19) at baseline and after perfusion with 4 different QT prolonging drugs at clinically relevant concentrations. Two proarrhythmic drugs in patients (bepridil and E4031) were compared with 2 nonproarrhythmic drugs (risperidone and verapamil). Both groups prolonged the QT (all P < 0.02), least with the proarrhythmic drug bepridil, reaffirming that QT is a poor predictor of TdP. In contrast, TDR was enhanced only by proarrhythmic drugs (P < 0.03). Increased TDR was due to a preferential prolongation of midmyocardial cell, relative to epicardial cell, APD, whereas nonproarrhythmic drugs similarly prolonged both cell types. In contrast to QT prolongation, augmentation of TDR was induced by proarrhythmic but not nonproarrhythmic drugs, suggesting TDR is a superior preclinical marker of proarrhythmic risk during drug development.     

Preclinical electrophysiology assays of mitemcinal (GM-611), a novel prokinetic agent derived from erythromycin

Mitemcinal (GM-611) is a novel erythromycin-derived prokinetic agent that acts as an agonist at the motilin receptor. Erythromycin has shown QT prolongation and torsades de pointes (TdP) in humans and cisapride, a second class of prokinetic agents typified by the 5-HT(4) receptor agonist, has been terminated due to TdP. In this study an extended series of safety pharmacology protocols and evaluations have been undertaken to assess the potential risk of mitemcinal on QT prolongation or proarrhythmic effects. Mitemcinal and its metabolites, GM-577 and GM-625, inhibited the human ether-a-go-go-related gene (HERG) tail current in a concentration-dependent manner with IC(50) values of 20.2, 41.7, and 55.0 microM, respectively. Administration of 10 mg/kg mitemcinal in anesthetized guinea pigs resulted in a slight prolongation of the monophasic action potential (MAP) duration during atrial pacing at the plasma concentration of mitemcinal 1.1 microM, with low maximum increases in MAPD(70) (6.6%) and MAPD(90) (4.6%) relative to vehicle. A 10-min infusion of 20 mg/kg of mitemcinal in a proarrhythmic rabbit model did not evoke TdP even when QT and corrected QT (QTc) intervals were significantly prolonged. In this study, the Cmax plasma-free concentration of mitemcinal indicates that the prolongation was more than 400-fold that of the therapeutic dose. Our findings of a wide safety margin and the absence of TdP within this margin suggest that mitemcinal may provide sufficient safety in clinical use.     

Unintended consequences of reducing QT-alert overload in a computerized physician order entry system

Purpose  After complaints of too many low-specificity drug-drug interaction (DDI) alerts on QT prolongation, the rules for QT alerting in the Dutch national drug database were restricted in 2007 to obviously QT-prolonging drugs. The aim of this virtual study was to investigate whether this adjustment would improve the identification of patients at risk of developing Torsades de Pointes (TdP) due to QT-prolonging drug combinations in a computerized physician order entry system (CPOE) and whether these new rules should be implemented. Methods  During a half-year study period, inpatients with overridden DDI alerts regarding QT prolongation and with an electrocardiogram recorded before and within 1 month of the alert override were included if they did not have a ventricular pacemaker and did not use the low-risk combination cotrimoxazole and tacrolimus. QT-interval prolongation and the risk of developing TdP were calculated for all patients and related to the number of patients for whom a QT-alert would be generated in the new situation with the restricted database. Results  Forty-nine patients (13%) met the inclusion criteria. In this study population, knowledge base-adjustment would reduce the number of alerts by 53%. However, the positive predictive value of QT alerts would not change (31% before and 30% after) and only 47% of the patients at risk of developing TdP would be identified in CPOEs using the adjusted knowledge base. Conclusion  The new rules for QT alerting would result in a poorer identification of patients at risk of developing TdP than the old rules. This is caused by the many non-drug-related risk factors for QT prolongation not being incorporated in CPOE alert generation. The partial contribution of all risk factors should be studied and used to create clinical rules for QT alerting with an acceptable positive predictive value.     

A new preclinical biomarker for risk of Torsades de Pointes: drug-induced reduction of the cardiac electromechanical window

Evaluation of new therapeutic agents for their potential to cause QT interval prolongation and drug-induced ventricular arrhythmia, like Torsades de Pointes (TdP), is a critical activity during drug development. The QT interval has been used as a surrogate biomarker to assess ventricular repolarization effects caused by drug-induced blockade of cardiac repolarizing currents, mainly I_Kr, but is imperfect in predicting proarrhythmia. Evidence suggests that left ventricular mechanical dysfunction may also contribute to ventricular arrhythmias; thus, electrical and mechanical alterations may have a role in drug-induced TdP. The electromechanical window (EMw) represents the time difference between the end of electrical systole (i.e. the QT interval) and the completion of ventricular relaxation (i.e. the QLVP_end interval), and appears to be a new potential biomarker for TdP risk. A reduction in the EMw (to negative values) has now been shown to be associated with the onset of TdP in an anaesthetized dog model of long QT1 syndrome. Therefore, the EMw represents a novel indicator of TdP risk that may add predictive value beyond assay of drug-induced QT interval prolongation.

LINKED ARTICLE

This article is a commentary on van der Linde et al., pp. 1444–1454 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2010.00934.x     

QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system

BACKGROUND: Recent case series have associated the synthetic opioid, methadone, with QT prolongation and torsades de pointes (TdP) ventricular arrhythmia. STUDY OBJECTIVE: To review and analyze adverse events (QT prolongation and TdP) reported to the Food and Drug Administration (FDA) to determine the patient characteristics, dosages of methadone, and outcomes of methadone-treated patients. METHODS: The study design was a retrieval and retrospective analysis of reports of adverse events associated with methadone voluntarily reported to the FDA MedWatch program from 1969 to October 2002. Reports were accessed via QSCAN (DrugLogic, Reston, VA), a commercially available software interface. RESULTS: In a total of 5,503 reports of adverse events associated with methadone, 43 (0.78%) noted the occurrence of TdP and 16 (0.29%) QT prolongation. Doses were reported in 42/59 (71%) of cases; mean dose was 410 +/- 349 mg/day (median 345, range 29-1680). The dosages for 10 of the 42 cases (29%) were within the recommended range for methadone maintenance treatment, 60-100 mg/day. Female gender, interacting medications, hypokalemia, hypomagnesemia, and structural heart disease, risk factors previously identified with other drugs known to cause TdP, were found in 44 (75%) cases. Most adverse events required hospitalization or resulted in prolonged hospitalization (28/59, 47%) and 5/59 (8%) were fatal. CONCLUSIONS: Cases of TdP associated with methadone have been reported to the FDA MedWatch system. Analysis of the cases provides evidence that prolonged QT and TdP can occur over a wide range of dosages including those usually recommended for addiction treatment.     

Acquired QT interval prolongation and HERG: implications for drug discovery and development

Putative interactions between the Human Ether-a-go-go Related Gene (HERG), QT interval prolongation and Torsades de Pointes (TdP) are now integral components of any discussion on drug safety. HERG encodes for the inwardly rectifying potassium channel (I_Kr), which is essential to the maintenance of normal cardiac function. HERG channel mutations are responsible for one form of familial long QT syndrome, a potentially deadly inherited cardiac disorder associated with TdP. Moreover, drug-induced (acquired) QT interval prolongation has been associated with an increase in the incidence of sudden unexplained deaths, with HERG inhibition implicated as the underlying cause. Subsequently, a number of non-cardiovascular drugs which induce QT interval prolongation and/or TdP have been withdrawn. However, a definitive link between HERG, QT interval prolongation and arrhythmogenesis has not been established. Nevertheless, this area is subject to ever increasing regulatory scrutiny. Here we review the relationship between HERG, long QT syndrome and TdP, together with a summary of the associated regulatory issues, and developments in pre-clinical screening.     

Strategies to reduce the risk of drug-induced QT interval prolongation: a pharmaceutical company perspective

Drug-induced prolongation of the QT interval is having a significant impact on the ability of the pharmaceutical industry to develop new drugs. The development implications for a compound causing a significant effect in the 'Thorough QT/QTc Study' -- as defined in the clinical regulatory guidance (ICH E14) -- are substantial. In view of this, and the fact that QT interval prolongation is linked to direct inhibition of the hERG channel, in the early stages of drug discovery the focus is on testing for and screening out hERG activity. This has led to understanding of how to produce low potency hERG blockers whilst retaining desirable properties. Despite this, a number of factors mean that when an integrated risk assessment is generated towards the end of the discovery phase (by conducting at least an in vivo QT assessment) a QT interval prolongation risk is still often apparent; inhibition of hERG channel trafficking and partitioning into cardiac tissue are just two confounding factors. However, emerging information suggests that hERG safety margins have high predictive value and that when hERG and in vivo non-clinical data are combined, their predictive value to man, whilst not perfect, is >80%. Although understanding the anomalies is important and is being addressed, of greater importance is developing a better understanding of TdP, with the aim of being able to predict TdP rather than using an imperfect surrogate marker (QT interval prolongation). Without an understanding of how to predict TdP risk, high-benefit drugs for serious indications may never be marketed.     

Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities

Safety pharmacology studies are performed to assess whether compounds may provoke severe arrhythmias (e.g. Torsades de Pointes, TdP) and sudden death in man. Although there is strong evidence that drugs inducing TdP in man prolong the QT interval in vivo and block the human ether-a-go-go-related gene (hERG) ion channel in vitro, not all drugs affecting the QT interval or the hERG will induce TdP. Nevertheless, QT-interval prolongation and hERG blockade currently represent the most accepted early risk biomarkers to deselect drugs. An extensive pharmacokinetic/pharmacodynamic (PK/PD) analysis is developed to understand moxifloxacin’s-induced effects on the QT interval by comparing the relationship between results of an in vitro patch-clamp model to in vivo models. The frequentist and the fully Bayesian estimation procedures were compared and provided similar performances when the best model selected in NONMEM is subsequently implemented in WinBUGS, which guarantees a straightforward calculation of the probability of QT-interval prolongation greater than 2.5 % (10 ms). The use of the percent threshold to account for the intrinsic differences between species and a new calculation of the probability curve are introduced. The concentration providing the 50 % probability indicates that dogs are more sensitive than humans to QT-interval prolongation. However, based on the drug effect, a clear distinction between species cannot be made. An operational PK/PD model of agonism was used to investigate the relationship between effects on the hERG and QT-interval prolongation in dogs. The proposed analysis contributes to establish a translational relationship that could potentially reduce the need for thorough QT studies.     

The electro-mechanical window in anaesthetized guinea pigs: a new marker in screening for Torsade de Pointes risk

BACKGROUND AND PURPOSE

QT prolongation is commonly used as a surrogate marker for Torsade de Pointes (TdP) risk of non-cardiovascular drugs. However, use of this indirect marker often leads to misinterpretation of the realistic TdP risk, as tested compounds may cause QT prolongation without evoking TdP in humans. A negative electro-mechanical (E-M) window has recently been proposed as an alternative risk marker for TdP in a canine LQT1 model. Here, we evaluated the E-M window in anaesthetized guinea pigs as a screening marker for TdP in humans.

EXPERIMENTAL APPROACH

The effects of various reference drugs and changes in body temperature on the E-M window were assessed in instrumented guinea pigs. The E-M window was defined as the delay between the duration of the electrical (QT interval) and mechanical (QLVP_end) systole.

KEY RESULTS

Drugs with known TdP liability (quinidine, haloperidol, domperidone, terfenadine, thioridazine and dofetilide), but not those with no TdP risk in humans (salbutamol and diltiazem) consistently decreased the E-M window. Interestingly, drugs with known clinical QT prolongation, but with low risk for TdP (amiodarone, moxifloxacin and ciprofloxacin) did not decrease the E-M window. Furthermore, the E-M window was minimally affected by changes in heart rate or body temperature.

CONCLUSIONS AND IMPLICATIONS

A decreased E-M window was consistently observed with drugs already known to have high TdP risk, but not with drugs with low or no TdP risk. These results suggest that the E-M window in anaesthetized guinea pigs is a risk marker for TdP in humans.     

Prediction of the risk of Torsade de Pointes using the model of isolated canine Purkinje fibres

Torsade de Pointes (TdP) is a well-described major risk associated with various kinds of drugs. However, prediction of this risk is still uncertain both in preclinical and clinical trials. We tested 45 reference compounds on the model of isolated canine Purkinje fibres. Of them, 22 are clearly associated and/or labelled with a risk of TdP, and 13 others are drugs with published clinical evidence of QT prolongation, with only one or two exceptional cases of TdP. The 10 remaining drugs are without reports of TdP and QT prolongation. The relevance of different indicators such as APD(90) increase, reverse use dependency, action potential triangulation or effect on V(max) was evaluated by comparison with available clinical data. Finally, a complex algorithm called TDPscreen and based on two subalgorithms corresponding to particular electrophysiological patterns was defined. This latter algorithm enabled a clear separation of drugs into three groups: (A) drugs with numerous or several reports (>2 cases) of TdP, (B) drugs causing QT prolongation and/or TdP only, the latter at a very low frequency (< or =2 cases), (C) drugs without reports of TdP or QT prolongation.The use of such an algorithm combined with a database accrued from reference compounds with available clinical data is suggested as a basis for testing new candidate drugs in the early stages of development for proarrhythmic risk prediction.