Drug Safety Research Laboratories, Takeda Chemical Industries, Ltd., Drug Safety Research Labs, 1785, Jusohonmachi 2chome, Yodogawaku, Osaka 532-8686, Japan
Received August 30, 2000; accepted November 9, 2000
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ABSTRACT |
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Key Words: torsades de pointes; dog model; astemizole; quinidine; anesthesia; drug safety.
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INTRODUCTION |
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On the other hand, there are at least 3 ion channels reported to be responsible for the pathogenesis of congenital LQTS in humans, which is classified into 6 types (LQT1-LQT6) according to the familial gene abnormalities. Mutations in the genes of KCNQ1 (Wang et al., 1996) and KCNE1 (Barhanin et al., 1996
; Sanguinetti et al., 1996
) that encode for the subunit of IKs are proved to be responsible for LQT1 and LQT5, respectively. LQT2 is due to abnormalities from a HERG mutation (Curran et al., 1995
) which encodes for the IKr channel (Sanguinetti et al., 1995
). LQT6 is due to mutation of the gene encoding the minK-related peptide that is considered to regulate the function of the pore of IKr (Abbott et al., 1999
). LQT3 is related to a mutation of SCN5A (Wang et al., 1995
) that produces defects in INa, the cardiac inward Na+ current. These may suggest that any drugs blocking these cardiac ion channels and acting as surrogate of any type of congenital LQTS may cause drug-induced LQTS. In fact, there is some experimental evidence that the IKs blocker, chromanol 293B, with isoproterenol (surrogate for LQT1; Shimizu and Antzelevitch, 1998), the IKr blockers, including sotalol and almokalant (surrogate for LQT2; Verduyn et al., 1997a), and the Na channel inactivation depressant anthopleurin-A (surrogates for LQT3; El-Sherif et al., 1996, 1997) induce TdP in some in vitro or in vivo experimental models.
From the standpoint of drug-safety evaluation, drug-induced TdP might be one of the most dangerous life-threatening adverse effects of any drug, preventing use of that drug unless it is developed for use only with careful electrocardiographic (ECG) monitoring. Hence, the risk that drugs could cause TdP in humans should be investigated in appropriate models that allow us to reasonably explore the risk. In particular, the dose (concentration)-dependency of any adverse effects and a pharmaco/toxicokinetic evaluation are essential to assess the safety margin and risk-benefit ratio. However, there have been few reports concerning the assessment of drug-induced TdP from the standpoint of safety evaluation. The purposes of this study were to develop an acute and sensitive model for drug-induced TdP capable of evaluating drugs for this risk. Because some anesthetic agents affect the inducibility of ventricular arrhythmias (Dawson et al., 1980; Hunt and Ross, 1988
) and ventricular repolarization, we investigated the effects of several common anesthetic agents on the inducibility of TdP in the presence of quinidine. The model was further validated using astemizole, which is known as one of the most potent HERG-related IKr channel blocker (Zhou et al., 1999
).
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MATERIALS AND METHODS |
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Experiment 1: Effects of sodium pentobarbital, halothane and isoflurane on susceptibility to quinidine-induced TdP.
Fifteen adult male beagle dogs weighing between 9.2 kg and 12.1 kg were used. They were divided into 3 groups, each consisting of 5 animals (Group P, for sodium pentobarbital; Group H, for halothane; Group I, for isoflurane). Animals in Group P were initially anesthetized with 35 mg/kg intravenous sodium pentobarbital (Nembutal®, Abbott), and maintained with an additional intravenous infusion of sodium pentobarbital at 3-6 mg/kg/h. After endotracheal intubation, dogs were ventilated with room air using a respiration pump (model 613D, Harvard). Animals in the Groups H and I were initially anesthetized with 15 mg/kg intravenous sodium thiopental (Ravonal®, Tanabe Pharmaceutical Co.). After endotracheal intubation, they were artificially ventilated with a mixture of oxygen and nitrous oxide (1:2) containing either halothane (Group H, vapor concentration 0.81.2%) or isoflurane (Group I, vapor concentration 0.81.4%) using inhalation anesthesia equipment (7900, Ohmeda).
The following methods were the same for the 3 groups. During the anesthesia, expiratory CO2 content and SpO2 were kept at around 4% and 90%, respectively, except after administration of quinidine at higher doses. A catheter-tipped micromanometer (MPC-500, Millar Instruments) was inserted into the femoral artery to measure arterial blood pressure (BP). A radio frequency ablation catheter (EPT5031T, EP Technology) was inserted via the femoral vein into the right atrium/ventricle. Complete atrioventricular (AV) block was induced by radio-frequency energy delivered from a generator (EPT-1000TC, EP Technology) by using a temperature control with maximal value at 60°C. The procedure was performed under echocardiographic (Fig. 1) and His-ECG guidance. After producing complete AV block, the ablation catheter was removed and replaced by a polyethylene catheter (C1, JMS) to collect blood samples for determination of plasma drug concentrations. A monophasic action potential (MAP)/pacing catheter (EPT1675P, EP Technology) was inserted via the jugular vein or carotid artery into the right or left ventricle to apply the programmed electrical stimulation (PES) at least 15 min before starting the experimental procedure. An ECG (lead II) was recorded throughout the experimental period.
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Parameters and measurements.
The catheter-tipped micromanometer-derived pressures, electrocardiographic signals, and MAP signals were relayed to biological amplifiers (1253A, NEC Medical Systems) in a polygraph system (NEC Medical Systems). All wave data from the polygraph system were recorded on a digital audiotape with a data recorder (RD-200T, TEAC) and digitized for subsequent analysis on a computer (Power Macintosh G3, Apple Computer) using the analyzing application (MP/VAS, Physio-Tech, Co.). The QT interval, QTc corrected by the method of Fridericia (1920), cycle length and blood pressure were measured with at least 3 continuous beats in each measurement point.
Induction of torsades de pointes.
The procedure to induce TdP was exactly the same in Experiments 1 and 2. After producing AV block and a stabilization period, 2 different types of PES protocol were applied using the MAP/pacing catheter. Type 1: Short (S1)-long (S2)-short (S3) sequence (the short coupling time was set at 3050 ms longer than the effective refractory period (ERP), and the long coupling time was set at 1000 or 1200 ms, depending on the cycle length of idioventricular rhythm (IVR)). Type 2; A train of 6 basic stimuli (S1) with an interval of 800 ms was followed by an extrastimulus (S2) with a coupling time 3050 ms longer than the ERP. The ERP was measured approximately by using the extrastimulus technique as described above (Type 2 PES protocol) at least 3 min before each measurement point. The process was repeated after shortening the S1S2 interval by 10 ms until failure to capture occurred. The ventricular ERP was defined as the longest S1S2 interval not capturing the ventricle. In cases where the ERP could not be determined because of induction of ventricular arrhythmia, the ERP was not measured, and expected values were used for both types of PES protocol. The stimulation pulses were rectangular in shape, twice the threshold voltage, and of 1-ms duration (Cardiac Stimulator, NEC Medical Systems). Both Type 1 and Type 2 PES protocols were repeated 5 times at each measuring point, so that a total of 10 PES trials were performed at each time. The definitions of ectopic beat (EB), multiple ectopic beats (mEBs), and TdP were as follows: EB, premature ventricular ectopic beat; mEBs, 2 or 4 continuous ectopic beats; TdP, 5 or more continuous EBs with a characteristic wave form of a twisting QRS complex around the electrical basis and occurring in the presence of a prolonged QT interval. The arrhythmias were judged inducible, even if the arrhythmia was observed only once.
Experimental protocol.
A summary of the experiment is shown in Figure 2. In Experiment 1, approximately 15 min after positioning of the MAP/pacing catheter at the apex of the left or right ventricle, a vehicle solution followed by quinidine at 0.3, 1 and 3 mg/kg was administered intravenously with an interval of 30 min using a cumulative escalating dosage schedule. Each dose was infused at a rate of 0.15 ml/kg/min for 10 min, and a 15-min washout period was carried out following administration of the highest dose. Induction of TdP by using the PES protocols, determinations of plasma drug concentrations, and analyses of ECG parameters and BP were performed before and just after each administration. In Experiment 2, astemizole was administered instead of quinidine in Experiment 1, and the procedures followed were the same as those in Experiment 1.
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Determination of plasma concentrations of quinidine and astemizole.
Blood samples of 1.5 ml were withdrawn from the femoral vein immediately after finishing the PES protocols at each measurement point. The sample was centrifuged (MX-151, Tomy Seiko Co.) at 12,000 rpm to obtain the plasma. Quinidine was determined by fluorescence polarization immunoassay using a commercially available kit (Dinabbott, Inc.) and the quantitation range was from 0.2 to 8.0 µg/ml. Astemizole, after being extracted from dog plasma with a mixture of diethyl ether and 1-chlorobutane (4:1, v/v) under slightly alkaline conditions, was determined by high-performance liquid chromatography with ultraviolet detection. The quantitation range was from 0.01 to 10 µg/ml.
Statistical analysis.
Data are presented as the mean ± SD. In Experiment 1, the effects of the anesthetic agents on the parameters measured were compared by one-way analysis of variance (ANOVA) followed by Fischer's PLSD test (Stat View 5.0). In Experiment 2, a Student's t-test was performed to compare the mean values in TdP-positive dogs with those in TdP-negative dogs. P values less than 0.05 or 0.01 were considered significant.
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RESULTS |
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Experiment 1: Incidence of Arrhythmias after Administration of Quinidine
Incidences of arrhythmias induced by PES protocols are summarized in Table 1. After administration of vehicle, no mEBs or TdP were induced in any group. In Group P, no TdP events were observed throughout the experiment. Only one animal in this group showed mEBs after administration of quinidine at 3 mg/kg. In Group H, TdP was induced in 1 out of 5 dogs after administration of quinidine at 0.3 mg/kg. The dog died due to ventricular fibrillation followed by spontaneous TdP during administration at 1 mg/kg. Quinidine at 1 mg/kg or more caused PES-induced TdP in 2 additional instances in this group. The total number of animals with TdP in this group was 3 out of 5 animals examined (60%). Multiple EBs were also noted in these 3 dogs, while there were no arrhythmias induced in the other 2 dogs in Group H. The typical configurations of the arrhythmias are presented in Figure 3
. In Group I, quinidine caused TdP in 1 of 5 animals (20%) while mEBs were noted in 3 of 5 dogs (60%).
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DISCUSSION |
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Anesthesia for This Model
Some common anesthetic agents are known to affect the QT interval or ventricular repolarization duration. Sodium pentobarbital, one of the most common anesthetic agents for pharmacological studies, has been reported to prolong ventricular repolarization in the in vitro arterially perfused ventricle (wedge preparation model; Shimizu et al., 1999). Halothane and isoflurane are also considered to affect ventricular repolarization duration (Gallagher, 1992; Hashimoto et al., 1997
; Michaloudis et al., 1998
), but the effects are still controversial. In the present study, the QT interval before administration of quinidine and the rate of prolongation after administration were greatest in dogs anesthetized with halothane. The incidence of TdP was also highest in dogs anesthetized with this agent. Although the reasons why halothane prolongs the QT interval and induces TdP in dogs have been unclear, our results may be consistent with evidence that halothane prolongs the QT interval in dogs (Gallagher, 1992
; Hashimoto et al., 1997
) and the halothane-anesthetized bradycardic dog could be a valuable model to discriminate drugs for their class III effects and proarrhythmic potencies (Weissenburger et al., 1999
). Regarding pentobarbital, an in vitro study using the wedge preparation model, has reported that pentobarbital prolongs ventricular repolarization time but prevents TdP induction by shortening transmural dispersion (Shimizu et al., 1999
). This is reasonable because TdP was not induced in dogs anesthetized with sodium pentobarbital in our study. In the case of isoflurane, the effects on repolarization duration and susceptibility to TdP were intermediate between sodium pentobarbital and halothane. From these results, we concluded, at present, that halothane is most suitable for our purpose because the most sensitive model is needed to assess the risk of drug-induced TdP.
Mechanism of TdP and the Role of PES in This Model
The mechanism of TdP has been unraveled over time using experimental models (El-Sherif and Turitto, 1999). Three major electrophysiological steps including "initiation," "maintenance," and "cessation" appear to underlie the mechanisms of induction of TdP. The initiation of the TdP has been considered to be due mostly to the triggered activity arising from the endomyocardium or Purkinje network (El-Sherif et al., 1996
, 1997
). It is well known that compounds prolonging repolarization, such as quinidine (Davidenko et al., 1989
; Roden and Hoffman, 1985
), terfenadine and astemizole (Salata et al., 1995
), cisapride (Puisieux et al., 1996
) can produce early afterdepolarization and trigger activity in in vitro studies. Early afterdepolarization-like waveform was observed not only in in vitro but also in in vivo by using MAP recordings after administration of sotalol (Verduyn et al., 1997b
), almokalant (Verduyn et al., 1997a
) and ibutilide (Chen et al., 1999
). From these findings, prolongation of repolarization has been strongly believed to act as a primary step for the generation of early afterdepolarization followed by triggered activity in LQTS. The maintenance and cessation of TdP have been recently unraveled by an anthopleurin-A canine model, a surrogate for LQT3, by using a 3-dimensional mapping technique (El-Sherif et al., 1996
, 1997
). These authors stated that the initial beat of polymorphic ventricular tachycardia consistently appeared as focal activity from a subendocardial site, whereas subsequent beats were due to reentrant excitation (El-Sherif et al., 1997
). The functional conduction block at the mid-myocardium, due to an increase in transmural dispersion of repolarization, especially at key adjacent sites, is thought to mainly contribute to the successful reentry for the maintenance of TdP (El-Sherif and Turitto, 1999
). In vitro studies using the wedge preparation revealed the role of the M cell on the re-entrant mechanisms of LQTS (Antzelevitch et al., 1999
; Shimizu and Antzelevitch, 1997
, 1998
). The termination of TdP could occur when all wave fronts meet the conduction block (El-Sherif et al., 1996
, 1997
). Therefore, it may be postulated that the prolongation of ventricular repolarization mainly involved in the initiation of TdP (triggered activity), and the focal conduction block at mid-myocardial region due to an increase in dispersion of repolarization underlie the maintenance mechanism of TdP.
When evaluating the risk of drug-induced TdP in humans, it might be reasonable to focus on effects on the maintenance mechanism of TdP rather than on the initiation mechanism, because some patients taking a drug might already be subject to spontaneous arrhythmias. In other words, a drug that increases the transmural dispersion of repolarization may cause TdP, supported by any type of premature contraction arising from any organic lesion or increased automaticity as well as triggered activity. Taking these factors into consideration, induction of TdP using PES protocols is thought to be useful for focusing on the maintenance mechanism of TdP. In the present study, some animals demonstrated not only PES-induced arrhythmias but also spontaneous bigeminy, mEBs and TdP during the observation period, suggesting that this model can provide us with some information about the effects on the initiation mechanism as well as on the maintenance mechanism.
Sensitivity and Specificity of This Model
The serum levels of quinidine in patients who suffered from TdP ranged from approximately 1 to 10 µg/ml (Bauman et al., 1984; Roden et al., 1986
; Thompson et al., 1988
), and the values were close to those of therapeutic range (2 to 6 µg/ml). The incidence of TdP in patients taking quinidine has been reported to be up to 8% (Bauman et al., 1984
; Roden et al., 1986
). On the other hand, in the present study, the lowest plasma concentration in one dog with TdP was approximately 0.2 µg/ml, and the incidence of TdP was 3 out of 5 dogs (60%) when the plasma concentration reached around 1 µg/ml. These data might indicate that this model is sensitive enough to assess the risk of drugs causing TdP in humans.
With respect to astemizole, the therapeutic plasma level of astemizole is around 5 ng/ml, while plasma concentrations of astemizole and/or its metabolites, after TdP, varied from 15 to 250 ng/ml (Hoppu et al., 1991; Ikeda et al., 1998
; Rao et al., 1994
; Simons et al., 1988
; Snook et al., 1988
). In the present study, however, astemizole at less than approximately 100 ng/ml of plasma concentrations, did not cause TdP in any dog, while those more than 200400 ng/ml induced TdP in 5 out of 10 animals (50%). Although the concentrations in patients, just at the onset of TdP, are still unclear, it seems that there is some difference in plasma concentrations between clinical cases and dogs in this study. Considering that the incidence of TdP in humans in this case seems to be very low compared to that for quinidine, the present results might be comparable to those for quinidine. In addition, the underlying potential differences in metabolism in dogs and humans may be related to this difference. For example, desmethylastemizole, the principal metabolite of astemizole, which is an equipotent blocker of HERG channels (Zhou et al., 1999
) is considered to accumulate and play an important role in the patients with astemizole-induced TdP, since the elimination time of this metabolite is 913 days. Furthermore, the concentrations of astemizole and its metabolites in cardiac myocytes in humans and dogs should be compared, in order to evaluate the influence of the accumulation of the drug in the heart. The model should be further validated using positive and negative control compounds in order to interpret the relevance of plasma levels that induce arrhythmias in this model to those in clinical risk.
In a total of 25 animals examined, there were no animals having arrhythmias such as mEBs or TdP after infusion of the vehicle except for only one case that revealed mEBs with a uniform configuration of the QRS complex. This arrhythmia could be due to chance because there were no arrhythmias after administration of astemizole in this animal. This may suggest that the incidence of false positives would be low in this model. On the other hand, there were several animals that did not show any arrhythmias even after administration of the drugs at the highest dose, indicating that the false-negative results might be occur in this model, and the results should be evaluated carefully when the number of animals examined is small.
Benefits and Defects of this Model
If the pharmacokinetic and metabolic profile of a drug is close to that in humans, an in vivo animal model would be valuable, since it allows us to assess not only the effect of the parent compound but also the combined effects with its metabolites, protein binding, etc., simultaneously. Furthermore, the effects of the drug on hemodynamics and pharmaco/toxicokinetic properties could be also evaluated simultaneously. These combined evaluations sometimes help us to assess the safety of the drug more practically than in in vitro models. One of the disadvantages to this model is that drugs cannot be administered orally, and the drug metabolism may be different if the drug is administered orally in the clinic. In this case, however, the intraduodenal route can be applied for this model in place of the oral route. Finally, it remains obscure whether this model is valuable for drugs affecting other repolarization-related ion channels such as the IKs, Ito, sodium, and calcium channels. Further studies are needed to clarify this.
Conclusion
The described acute canine model for drug-induced TdP using halothane anesthesia, complete AV block, PES protocol and simultaneous measurements of plasma drug concentrations is considered to be valuable for assessing the risk of drugs, especially IKr blockers to induce TdP in humans. The model should be further validated using positive and negative control compounds in order to interpret the relevance of plasma levels that induce arrhythmias in this model to those in clinical risk.
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ACKNOWLEDGMENTS |
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NOTES |
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