The consortium advocates that the accumulated information should be made available to the different stakeholders and that the workflow is maintained to investigate the arrhythmogenic potential of other drugs much faster. Project Context and Objectives: Cardiac ventricular arrhythmia as a side effect of anti-arrhythmic and non-antiarrhythmic drugs has become a major pharmacological safety concern for the pharmaceutical industry and the health regulatory authorities1,2.
Among drug-induced arrhythmias, Torsade de Pointes TdP is by far the most important and worrisome. Electrophysiology of heart rhythm The rhythm of the heart is controlled by a balance of ions flowing into and out of individual cardiac cells.
Most of this ionic traffic flows through membrane-spanning proteins known as voltage-dependent ion channels. When they work in concert, the activity of these ion channels gives rise to the shape and duration of the action potential on the cellular level and to the electrocardiogram ECG measured clinically. Figure 1: Action potential and ion in-outflow Torsade de Pointes and risk factors Torsade de Pointes is a polymorphic ventricular tachycardia, if it occurs it may lead to syncope, seizure, ventricular fibrillation and sudden death3.
The most important risk factor for TdP is prolongation of the QT interval, which can be congenital but is mostly drug-induced. Other risk factors are: hypokalaemia, heart failure, myocardial infarction, diabetes mellitus and bradycardia3, Prolongation of the QT interval may result in early after depolarizations EAD , which in turn may induce re-entry and thereby provoke Torsade de Pointes and fatal ventricular fibrillation leading to sudden cardiac death 1,9, Although QTc QT interval corrected for the heart rate 14 prolongation is almost always present in cases with TdP3 and in itself has been directly associated with sudden cardiac death in epidemiological studies15,16, QTc prolongation itself is not a perfect predictive marker of TdP risk TdP liability.
Many persons have QTc prolongation and will not develop TdP. Moreover, there is no consensus on the magnitude of prolongation raising concern, although the threshold on the extent of prolongation for regulatory purposes is a mean increase of 10 ms. Some drugs prolong the QTc interval, but appear devoid of torsadogenic effects e. It is to be expected that both drug as well as person based risk factors may interact to cause TdP.
QTc prolongation and mechanisms The vast majority of drugs associated with QTc prolongation are thought to act by reducing the IKr current in the heart3. Due to the role of hERG in causing QTc prolongation and potentially TdP and the availability of in vitro methods to model hERG binding, a common first step of screening drugs for potential torsadogenic effects is to look at hERG affinity Terfenadine is a potent IKr blocker, but usually does not prolong the QTc interval because it is readily transformed into a metabolite with no QT liability.
In any case, because of the possible occurrence of drug interactions diseases that inhibit metabolism and due to the existence of alternatives, its use has been restricted 9,11, These actions may be either direct by blunting early after depolarizations or indirect by blunting the prolongation of the action potential In addition, the assessment of the net arrhythmic effects should also comprise pharmacokinetic aspects including metabolism since a very low baseline pro-arrhythmic effects may become clinically important in case of drug interactions leading to higher than expected plasma levels.
Regulatory actions In the s, large case series of TdP were accumulated, which showed the overwhelming preponderance of non-antiarrhythmic drug therapy to cause TdP. Non-antiarrhythmic drugs that have been associated with TdP and sudden death include antipsychotics7,19,20, antihistamines especially diphenhydramine and astemizole 18,21, anti-infectives macrolides, quinolones, imidazole antifungals and gastrointestinal drugs cisapride and domperidone 22, but incidence with non-antiarrhythmic drugs whenever available is less common per , 5, This long and growing list of non-antiarrhythmic drugs linked to TdP has contributed to the unjustified view that QT prolongation is usually an effect of a whole therapeutic class, whereas, in many cases, it is displayed only by specific compounds within a given class.
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Rarely however, all drugs in the entire class are investigated. In recent years, a number of blockbuster antipsychotic, antihistaminic, gastrointestinal and anti-infective drugs e. This has resulted in health concerns for patients as well as billions of dollars of lost revenues for the pharmaceutical industry4. The relative rarity of drug-induced TdP in non-antiarrhythmic drugs5 and our imperfect prediction of risk for a given individual, make this a particularly vexing problem for clinicians.
Several attempts have been made to list the drugs that are associated with QTc prolongation and cardiac arrhythmias1, Although these lists provide some ranking, the absolute and relative risks of TdP and sudden death for the listed drugs are mostly unknown as most are based on case reports and incomplete evidence. In the absence of complete explanatory factors but the link with QTc prolongation, regulatory agencies have taken several measures to reduce the risk of licensing potentially torsadogenic drugs by implementing guidelines ICH S7B and ICH E14 for the early identification of TdP.
This involves a battery of preclinical and clinical tests in vitro and in vivo models of a delayed cardiac ventricular repolarization, or QTc interval prolongation, as surrogate biomarkers of TdP risk6. However the link between the primary abnormalities such as hERG channel inhibition and TdP or sudden death is a complex one, as it is modulated by a number of factors. The low specificity i. Some attempts were made to associate in vitro measures with clinical measures or spontaneous reports of ventricular arrhythmia or sudden death but a systematic comprehensive assessment that includes epidemiological studies as well was still lacking11, Since apparently not all TdP can be predicted accurately by either hERG blockade or QTc prolongation, it is likely that other genetic and environmental risk factors may affect or modify the association between QTc-prolongation, TdP and sudden death.
Genetics and drug-induced long QT syndrome, TdP or cardiac arrest Until the start of ARITMO, the search for sequence variants contributing to sudden death SD risk was restricted to several candidate genes known for their role in arrhythmogenesis. Yet, the relatively small size of existing sudden death collections and etiologic heterogeneity limit the statistical power to detect causal variants. Therefore, initial attention has focused on quantitative sudden death risk factors available in large cohorts, such as QT prolongation.
Hundreds of mutations in 10 genes linked to the long-QT syndrome have been identified The prevalence of mutations is at least 1 per persons, however most remain asymptomatic during life The interaction between LQT mutations or NOS1AP variants and drug-induced symptomatic QT prolongation is largely unknown due to the rarity of the event and the lack of large case series. The identification of common variants that modify risk of drug-induced arrhythmia would be exciting from a clinical perspective. Genetic variation is now well-recognized as one source of variable response to drug therapy including variable susceptibility to adverse drug reactions.
One recent study evaluated the frequency of rare non-synonymous variants in genes contributing to the maintenance of heart rhythm in cases of diLQTS using targeted capture coupled to next-generation sequencing. The authors concluded that the rare variation in genes responsible for congenital arrhythmia syndromes is frequent in diLQTS and their findings demonstrate that diLQTS is a pharmacogenomic syndrome predisposed by rare genetic variants. The specific objectives were: 1 To predict QT liability and TdP propensity for study drugs via in silico modelling.
Project Results: 1. To this aim, a list of all drugs to be investigated was created according to ATC classification by considering: 1 all V level ATC codes in the classes J anti-infectives for systemic use, except for vaccines , N05A antipsycotics, except for lithium N05AN , P01 antiprotozoals and R06A antihistamines for systemic use ; 2 V level ATC codes of molecules belonging to the aforementioned pharmacological groups, but included in other ATC classes, provided that they can have systemic effects e. A02BD which corresponds to combinations of antibacterials used in the treatment of peptic ulcer.
This broad list was taken into account in the activities of all the Work Packages except for WP6 Literature review and docking of molecules WP 7. The narrow ARITMO drug list comprising drugs has been prepared using various criteria based on frequency of use and publications or thorough QT studies. Since the different workpackages use different type of data, that may be coded with different terminologies. This approach offered the opportunity to provide consortium with a shared semantic basis for the creation of queries, to be adapted to the heterogeneity of different databases.
ARITMO covariates As covariates of interest, we identified all the potential risk factors of QT prolongation, Torsade de pointes, ventricular fibrillation and sudden cardiac death. As there is a common pathway leading from QT prolongation to sudden cardiac death we did not distinguish at this stage the risk factors for individual study outcomes.
Apart from the risk factors of QT prolongation and related cardiac arrhythmias, we identified also the main indication for use of the different study drugs. The RRE allows for loading, retrieving, extracting, and transforming of the data. All partners signed confidentiality agreements.
Figure 4: Remote Research Environment 1. However other ion channels are important as well and there is evidence of cases of ventricular arrhythmia arising from pharmacological blockade of ion channels different from hERG: particularly susceptible are I fast sodium channel, Nav1.
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Blockade of these channels will lead to anomalies in the action potential raising the risk of arrhythmic episodes. Accordingly it has been suggested that multi-channel effects must be considered when evaluating arrhythmic risk see figure 5. Three targets with established impact on the cardiac profile were selected to set up the risk profile, hERG, Nav1.
Data on target interactions were retrieved and described in D7. For Nav1. In silico target profiling could be used to predict 36 drugs in the hERG model, 10 Cav1. The close correlation between free plasma concentrations associated with QT prolongation in both dog and man and the concentration associated with inhibition of the hERG channel in vitro have been demonstrated for terfenadine, terodiline and cisapride. An analysis of available data relating to QT prolongation demonstrated the dependence of QT prolongation on free plasma concentrations and lent support to the application of a fold safety multiple between therapeutic activity and concentration causing QT prolongation.
This can be further refined by the incorporation of a pharmacokinetic component to provide greater assurance that clinical exposure at proposed therapeutic doses will not approach free plasma concentrations expected to cause this adverse pharmacology.
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The results show that for the drugs for which we have data we generally have a lot of replicate measures. However a complete set of the core PK parameters for a drug i. For compounds we could provide the full profile of the above parameters, and for another one parameter were lacking.
Data were made available in an excel sheet D7. This method can also be adopted by regulators to periodically monitor and prioritize potential signals arising from spontaneous reporting systems, especially for newly marketed drugs. Spontaneous reports of drug-event combinations are collected by drug companies and at a regional, national and international level through different databases. Each European country collects its own reports in a national spontaneous reporting database, although also international archives gather reports originating from different countries.
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The Uppsala Monitoring Centre in Sweden is responsible for the worldwide gathering of all serious ADRs received by regulatory authorities and companies. Two different approaches were used for providing the required data for each ARITMO drug while using the multiple resources: a traditional approach and a novel approach. The list of scores is available in deliverable D 3. Novel approach. A new ARITMO Pharmacovigilance Score was developed that goes beyond the current standard and that allows for integration of evidence from multiple sources see figures 7 and 8. Criterium Description Threshold Value Coefficient 1.
The full description of criteria and relevant information was provided in a dedicated Deliverable D3. Figure 8: approach for novel pharmacovigilance score left and the number of drugs for which a novel PhV score could be calculated. The score was calculated by integrating evidence from 5 databases, and figure 8 shows that the combination of those databases allows for information on many more drugs than what would have been possible from a single source. A score for a drug could only be calculated if there were at least 3 case reports in each of the databases. Overall, drugs received in integrated score and a value of uncertainty i.
Use of the novel PhV score allowed for graphical display of the score across the classes figure 9. Notably, there are inter and intra-class differences in the distribution of the scores: for instance, nine antipsychotics received a score higher than moxifloxacin the drug with the highest score among antibacterials.
Among antipsychotics, the score spans from 0. Please remember that, for WP8 purpose, we also identified low risk drugs, i. A matched case-control design was chosen to analyse the data. Two different case definitions were established to which the different data sources contributed to different extent depending on their data availability: Case definition 1 was based on ECG-confirmed cases with moderate or severe QTc prolongation with clinical symptoms including TdP and VF, or severe QTc prolongation without clinical symptoms.
Case definition 2 included patients with evidence of QTc prolongation as found via free-text search in the electronic healthcare databases or QTc prolongation comparing two standardised subsequent ECG readings. Controls were ascertained from the same data source and matched by age and sex. Exposure to the ARITMO drugs anti-infectives, antihistamines and antipsychotics as well as to all other drugs was analysed.
As these analyses suffered from limited study power for case definition 1, but also from instable statistical models for case definition 2, another approach was chosen presented here. In this second approach, drugs were grouped according to their indication and by their known or assumed potential to cause QTc prolongation or TdP. For all these analyses, as confounders, cardiologic and other comorbidities were taken into account. For case definitions 1 and 2, regression models were fitted regarding the different exposure definitions. Second, the odds ratio OR for current use i.
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