The pre-clinical assessment of QT interval prolongation: a comparison of in vitro and in vivo methods

1998 ◽  
Vol 17 (12) ◽  
pp. 677-680 ◽  
Author(s):  
A Stewart Davis
Keyword(s):  
Clinical Assessment ◽  
Action Potential Duration ◽  
Qt Interval ◽  
Qt Prolongation ◽  
New Drugs ◽  
Interval Prolongation ◽  
In Vitro Methods ◽  
Qt Interval Prolongation

The literature was searched for in vivo dog studies reporting QT prolongation and in vitro studies reporting increased myocardial action potential duration, which indicates the potential to prolong QT interval, for nine non-cardiac drugs that have been reported to produce QT prolongation in man. The drugs were: astemizole; terfenadine; erythromycin; sparfloxacin; cisapride; probucol; terodiline; risperidone and sertindole. 1 There were reports of the appropriate finding with in vitro methods for six of the drugs and with in vivo methods for seven of the drugs. No reports were found concerning the remaining drugs with each method. This indicates that both methods are effective and each method would have correctly identified the drugs in question as having the potential to prolong the QT interval in man in all cases for which studies were reported. 2 This suggests that, if properly conducted, either method alone is sufficient for the pre-clinical assessment of QT interval prolongation. This does not support the routine use of both methods before the administration of new drugs to man.

Effects of probucol, a typical hERG expression inhibitor, on in vivo QT interval prolongation in conscious dogs

2013 ◽  
Vol 720 (1-3) ◽  
pp. 29-37 ◽  
Author(s):  
Hisashi Nogawa ◽  
Tomoyuki Kawai ◽  
Miho Yajima ◽  
Masahiro Miura ◽  
Tetsurou Ogawa ◽  
...  
Keyword(s):  
Qt Interval ◽  
Conscious Dogs ◽  
Interval Prolongation ◽  
Qt Interval Prolongation

What is the role of QTc prolongation assessment in new drugs development phase I oncology trials?

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2006-2006
Author(s):  
G. Curigliano ◽  
C. Cipolla ◽  
C. Sessa ◽  
C. Noberasco ◽  
T. De Pas ◽  
...  
Keyword(s):  
Phase I ◽  
Qt Interval ◽  
Phase I Study ◽  
Qt Prolongation ◽  
New Drugs ◽  
Accurate Information ◽  
Investigational Drug ◽  
Qtc Interval ◽  
Qtc Prolongation ◽  
Qt Interval Prolongation

2006 Background: QT interval prolongation associated with “torsades de pointes” (TdP) has been a common cause of withdrawal from the market for several promising drugs. We determined the degree of QT prolongation in patients treated within a phase I study with a thioxanthone derivative known to have arrhythmogenic potential. Methods: Clinical data and serial ECGs from 31 patients with advanced tumors who received 86 courses of investigational drug were prospectively reviewed. The drug has been administered intravenously over 24 hours every 3 weeks. Patients have been on a 24 hour Holter monitor until 24 hours after infusion was complete. Three baseline ECGs were done and compared to those every 6 hours during therapy and once 6 hours after the infusion was complete. ECGs were read at a central lab according to a standard protocol. All QT measurements were then corrected for heart rate (QTc) using Bazett’s formula (QTc = QT interval divided by the square root of the R-R interval). Results: Overall,843 ECG tracings were obtained, all evaluable for analysis. No basal ECG showed significant abnormalities. Prolonged QT intervals developed in 2 patients without clinical symptoms (1 patient had intervals 500 milliseconds).In both cases it was associated with the maximum concentration of the drug. Compared with baseline, the QTc interval was prolonged by 30 to 60 milliseconds in 20% of total tracings, and by more than 60 milliseconds in 2% of ECGs. In patients receiving multiple courses, QTc intervals returned to pretreatment levels before the second course. Conclusions: The assessment of QTc prolongation was a major effort in this study but produced an accurate information about such event. In phase I study such an effort is justified when arrhythmogenicity is suspected. The timing of collection of ECGs should be guided by the available preclinical information about the pharmacokinetic profile of the drug. Nevertheless uncertainty remains regarding the specific relationship between the degree of QT prolongation and the risk of life-threatening arrhythmias. The decision to use the drug ultimately has to be based on an estimation of the perceived risk relative to expected benefits for patients. No significant financial relationships to disclose.

scholarly journals Measurements of blood pressure and electrocardiogram in conscious freely moving guineapigs: a model for screening QT interval prolongation effects

2007 ◽  
Vol 41 (4) ◽  
pp. 470-480 ◽  
Author(s):  
P Hess ◽  
M Rey ◽  
D Wanner ◽  
B Steiner ◽  
M Clozel
Keyword(s):  
Blood Pressure ◽  
Qt Interval ◽  
Abdominal Cavity ◽  
Good Alternative ◽  
Suitable Model ◽  
Interval Prolongation ◽  
Qt Interval Prolongation ◽  
Freely Moving ◽  
Electrocardiographic Intervals

The pro-arrhythmic risk inherent to a new drug must be assessed at an early preclinical stage. Telemetry system implantation is a method widely used in vivo in various species. The present study was designed to assess whether conscious freely moving guineapigs can be used to predict QT prolongation in vivo. The guineapig has three advantages over the dog and the primate. First, it has specific ion channels similar to man; second, a smaller amount of test article is required for the investigation and third, its housing is less expensive. Under sterile conditions and isoflurane anaesthesia, telemetry transmitters were implanted intraperitoneally in male Dunkin Hartley guineapigs. Blood pressure, heart rate and electrocardiographic intervals were measured from two days up to eight months. Chronic implantation of the telemetry device did not lead to anatomic or macroscopic alterations in the abdominal cavity and no inflammation of the peritoneum or infection was observed. Four reference compounds were used: three positive (sotalol, terfenadine and dofetilide) and one negative reference (enalapril). Single oral administration of all three positive references dose-dependently induced bradycardia and QT corrected (QTc) prolongation. In contrast, neither enalapril nor its vehicle prolonged the QTc. These results demonstrate that the guineapig is both a suitable model and a good alternative to dogs or primates to assess the potential of compounds for QT interval prolongation in the early stages of drug development.

scholarly journals Tyrosine Kinase Inhibitors-Induced Arrhythmias: From Molecular Mechanisms, Pharmacokinetics to Therapeutic Strategies

2021 ◽  
Vol 8 ◽  
Author(s):  
Mengfei Cheng ◽  
Fang Yang ◽  
Jiahui Liu ◽  
Dan Yang ◽  
Shuo Zhang ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Qt Interval ◽  
Clinical Evidence ◽  
Kinase Inhibitors ◽  
Qt Prolongation ◽  
Small Sample ◽  
Interval Prolongation ◽  
Preclinical Trial ◽  
Qt Interval Prolongation

With the development of anti-tumor drugs, tyrosine kinase inhibitors (TKIs) are an indispensable part of targeted therapy. They can be superior to traditional chemotherapeutic drugs in selectivity, safety, and efficacy. However, they have been found to be associated with serious adverse effects in use, such as myocardial infarction, fluid retention, hypertension, and rash. Although TKIs induced arrhythmia with a lower incidence than other cardiovascular diseases, much clinical evidence indicated that adequate attention and management should be provided to patients. This review focuses on QT interval prolongation and atrial fibrillation (AF) which are conveniently monitored in clinical practice. We collected data about TKIs, and analyzed the molecule mechanism, discussed the actual clinical evidence and drug-drug interaction, and provided countermeasures to QT interval prolongation and AF. We also pooled data to show that both QT prolongation and AF are related to their multi-target effects. Furthermore, more than 30 TKIs were approved by the FDA, but most of the novel drugs had a small sample size in the preclinical trial and risk/benefit assessments were not perfect, which led to a suspension after listing, like nilotinib. Similarly, vandetanib exhibits the most significant QT prolongation and ibrutinib exhibits the highest incidence in AF, but does not receive enough attention during treatment.

scholarly journals The QT long syndrome: clinical and diagnostic aspect

2021 ◽  
Vol 69 (1) ◽  
Author(s):  
Constantin Martiniuc ◽  
◽  
Serghei Pisarenco ◽  
Iurie Simionica ◽  
◽  
...  
Keyword(s):  
Qt Interval ◽  
Torsade De Pointes ◽  
Qt Prolongation ◽  
Current Data ◽  
Polymorphic Ventricular Tachycardia ◽  
Interval Prolongation ◽  
Qt Interval Prolongation ◽  
Increased Risk ◽  
Wide Range ◽  
Life Threatening

QT interval prolongation is a predictor of the life-threatening cardiac arrhythmias — polymorphic ventricular tachycardia (torsade de pointes). Long QT syndrome may be congenital or acquired. It is known that a wide range of both antiarrhythmic and non-cardiac medications might lead to QT interval prolongation. List of drugs that cause QT prolongation is constantly growing and being updated. The review contains current data on the clinical significance of the control of QT interval duration within drug therapy. Clinical conditions associated with an increased risk of QT interval prolongation are described. Drugs that can induce QT prolongation are also discussed.

scholarly journals QT Interval Prolongation and Torsade De Pointes in Patients with COVID-19 treated with Hydroxychloroquine/Azithromycin

2020 ◽  
Author(s):  
Ehud Chorin ◽  
Lalit Wadhwani ◽  
Silvia Magnani ◽  
Matthew Dai ◽  
Eric Shulman ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Qt Interval ◽  
Potential Benefit ◽  
Drug Exposure ◽  
Torsade De Pointes ◽  
Careful Consideration ◽  
Qt Prolongation ◽  
Interval Prolongation ◽  
Qtc Prolongation ◽  
Qt Interval Prolongation

AbstractBackgroundThe emergence of the COVID-19 pandemic has resulted in over two million affected and over 150 thousand deaths to date. There is no known effective therapy for the disease. Initial reports suggesting the potential benefit of Hydroxychloroquine/Azithromycin (HY/AZ) have resulted in massive adoption of this combination worldwide. However, while the true efficacy of this regimen is unknown, initial reports have raised concerns regarding the potential risk of QT prolongation and induction of torsade de pointes (TdP).MethodsThis is a multicenter retrospective study of 251 patients with COVID-19 treated with HY/AZ. We reviewed ECG tracings from baseline and until 3 days after completion of therapy to determine the progression of QTc and incidence of arrhythmia and mortality.ResultsQTc prolonged in parallel with increasing drug exposure and incompletely shortened after its completion. Extreme new QTc prolongation to > 500 ms, a known marker of high risk for TdP had developed in 15.9% of patients. One patient developed TdP requiring emergent cardioversion. Seven patients required premature termination of therapy. The baseline QTc of patients exhibiting QTc prolongation of > 60 ms was normal.ConclusionThe combination of HY/AZ significantly prolongs the QTc in patients with COVID-19. This prolongation may be responsible for life threating arrhythmia in the form of TdP. This risk mandates careful consideration of HY/AZ therapy in lights of its unproven efficacy. Strict QTc monitoring should be performed if the regimen is given.

scholarly journals Risk of QT Prolongation through Drug-drug Interactions between Hydroxychloroquine and Concomitant Drugs Prescribed in Real-world Practice

2020 ◽  
Author(s):  
Byung Jin Choi ◽  
Yeryung Koo ◽  
Tae Young Kim ◽  
Wou Young Chung ◽  
Yun Jung Jung ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Real World ◽  
Qt Interval ◽  
Qt Prolongation ◽  
Qtc Interval ◽  
Interval Prolongation ◽  
Qt Interval Prolongation ◽  
Life Threatening ◽  
Alternative Drugs

Abstract Background: Hydroxychloroquine has recently received attention as a treatment for COVID-19. However, hydroxychloroquine may prolong the QTc interval, thus increasing the risk of life-threatening arrhythmia. Many patients with COVID-19 have comorbidities, necessitating the use of several drugs simultaneously with hydroxychloroquine. However, the risk of QT prolongation due to drug-drug interactions (DDIs) between hydroxychloroquine and these co-medications has not been identified. Therefore, it is necessary to investigate the risk of QT interval prolongation due to DDIs between hydroxychloroquine and frequently used concurrent drugs.Methods and Results: Using 447,632 patients and 1,040,752 electrocardiograms, we investigated the risk of QT prolongation due to DDIs between hydroxychloroquine and 118 concurrent drugs frequently used in real-world practice. In the analysis, we observed that 11 drugs (trimebutine, tacrolimus, tramadol, rosuvastatin, ciclosporin, sulfasalazine, rofecoxib, diltiazem, piperacillin/tazobactam, and isoniazid) show DDIs with hydroxychloroquine in the direction of QT prolongation.Conclusions: We found 11 drugs that show significant (p <0.05) DDIs with hydroxychloroquine, thereby increasing the risk of QT prolongation in patients. It is necessary to consider prescribing alternative drugs that have less DDI when these drugs are concurrently administered with hydroxychloroquine. Further investigation is needed to assess more profoundly the risk of QT prolongation due to DDI with hydroxychloroquine of each drug that we found in this analysis.

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