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Dive into the research topics where Gopi Krishna Panicker is active.

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Featured researches published by Gopi Krishna Panicker.


British Journal of Pharmacology | 2010

Update on the evaluation of a new drug for effects on cardiac repolarization in humans: issues in early drug development

Vaibhav Salvi; Dilip R. Karnad; Gopi Krishna Panicker; Snehal Kothari

Following reports of death from cardiac arrhythmias with drugs like terfenadine and cisapride, the International Conference for Harmonization formulated a guidance (E14) document. This specifies that all new drugs must undergo a ‘thorough QT/QTc’ (TQT) study to detect drug‐induced QT prolongation, a surrogate marker of ventricular tachycardia, especially torsades de pointes (TdPs). With better understanding of data from several completed TQT studies, regulatory requirements have undergone some changes since the E14 guidance was implemented in October 2005. This article reviews the implications of the E14 guidance and the changes in its interpretation including choice of baseline QT, demonstration of assay sensitivity, statistical analysis of the effect of new drug and positive control, and PK‐PD modelling. Some issues like use of automated QT measurements remain unresolved. Pharmaceutical companies too are modifying Phase 1 studies to detect QTc liability early in order to save time and resources. After the E14 guidance, development of several drugs that prolong QTc by >5 ms is being abandoned by sponsors. However, all drugs that prolong the QT interval do not increase risk of TdP. Researchers in regulatory agencies, academia and industry are working to find better biomarkers of drug‐induced TdP which could prevent many useful drugs from being prematurely abandoned. Drug‐induced TdP is a rare occurrence. With fewer drugs that prolong QT interval reaching the licensing stage, knowing which of these drugs are torsadogenic is proving to be elusive. Thus, paradoxically, the effectiveness of the E14 guidance itself has made prospective validation of new biomarkers difficult.


British Journal of Clinical Pharmacology | 2014

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modelling in a phase 1 study with oral rac-sotalol.

Borje Darpo; Dilip R. Karnad; Fabio Badilini; Jeff Florian; Christine Garnett; Snehal Kothari; Gopi Krishna Panicker; Nenad Sarapa

AIM To study the differences in QTc interval on ECG in response to a single oral dose of rac-sotalol in men and women. METHODS Continuous 12-lead ECGs were recorded in 28 men and 11 women on a separate baseline day and following a single oral dose of 160 mg rac-sotalol on the following day. ECGs were extracted at prespecified time points and upsampled to 1000 Hz and analyzed manually in a central ECG laboratory on the superimposed median beat. Concentration-QTc analyses were performed using a linear mixed effects model. RESULTS Rac-sotalol produced a significant reduction in heart rate in men and in women. An individual correction method (QTc I) most effectively removed the heart rate dependency of the QTc interval. Mean QTc I was 10 to 15 ms longer in women at all time points on the baseline day. Rac-sotalol significantly prolonged QTc I in both genders. The largest mean change in QTc I (ΔQTc I) was greater in females (68 ms (95% confidence interval (CI) 59, 76 ms) vs. 27 ms (95% CI 22, 32 ms) in males). Peak rac-sotalol plasma concentration was higher in women than in men (mean Cmax 1.8 μg ml(-1) (range 1.1-2.8) vs. 1.4 μg ml(-1) (range 0.9-1.9), P = 0.0009). The slope of the concentration-ΔQTc I relationship was steeper in women (30 ms per μg ml(-1) vs. 23 ms per μg ml(-1) in men; P = 0.0135). CONCLUSIONS The study provides evidence for a greater intrinsic sensitivity to rac-sotalol in women than in men for drug-induced delay in cardiac repolarization.


Journal of Electrocardiology | 2009

Intra- and interreader variability in QT interval measurement by tangent and threshold methods in a central electrocardiogram laboratory

Gopi Krishna Panicker; Dilip R. Karnad; Mili Natekar; Snehal Kothari; Dhiraj Narula; Yash Lokhandwala

BACKGROUND The QT interval can be measured by tangent (QT(Tan)) and threshold (QT(Thr)) methods; the better method is the one with lower reader variability. METHODS QT(Tan) and QT(Thr) were measured twice in 100 digital electrocardiograms (ECGs) by 8 experienced readers in a central laboratory. For QT(Thr), the end of the T wave was the point where the T wave reached the isoelectric baseline; for QT(Tan), it was the point where a line from the peak of the T wave through the steepest part of the descending limb intercepted the isoelectric baseline. RESULTS The average absolute intrareader variability ranged from 3.4 to 6.9 milliseconds for QT(Tan) and from 3.5 to 5.2 milliseconds for QT(Thr). By analysis of variance, intrareader SD of QT(Tan) was 7.0 and 7.5 milliseconds for QT(Thr); interreader SD was 13.1 milliseconds for QT(Tan) and 11.9 milliseconds for QT(Thr). QT(Tan) was shorter than QT(Thr) in 96 of the 100 ECGs, it exceeded QT(Thr) in 4 ECGs, which had prominent U waves. CONCLUSIONS For trained readers in a central ECG laboratory using sophisticated on-screen tools for QT measurement in high-quality digital ECGs, between- and within-reader variability are comparable for QT(Tan) and QT(Thr). However, QT(Tan) is consistently shorter than QT(Thr) by up to 10 milliseconds.


Journal of Electrocardiology | 2011

Comparison of 5 methods of QT interval measurements on electrocardiograms from a thorough QT/QTc study: effect on assay sensitivity and categorical outliers

Vaibhav Salvi; Dilip R. Karnad; Gopi Krishna Panicker; Mili Natekar; Pooja Hingorani; Vaibhav Kerkar; Arumugam Ramasamy; Michiel de Vries; Troy L. ZumBrunnen; Snehal Kothari; Dhiraj Narula

INTRODUCTION We studied moxifloxacin-induced QT prolongation and proportion of categorical QTc outliers when 5 methods of QT measurement were used to analyze electrocardiograms (ECGs) from a thorough QT study. METHODS QT interval was measured by the threshold, tangent, superimposed median beat, automated global median beat, and longest QT methods in a central ECG laboratory in 2730 digital ECGs from 39 subjects during placebo and moxifloxacin treatment. RESULTS All 5 methods were able to demonstrate statistically significant moxifloxacin-induced QTcF prolongation. However, lower bound of 95% 1-sided confidence interval of QTcF prolongation did not exceed 5 milliseconds with the longest QT method. More QTcF outliers were observed with the longest QT and tangent methods, whereas the other 3 methods were comparable. QTcF values greater than 500 milliseconds were observed only with moxifloxacin by the tangent method, and with moxifloxacin and placebo by the longest QT method. CONCLUSION The method of QT measurement must be considered when interpreting individual thorough QT/QTc studies.


Heart Rhythm | 2012

Early repolarization and short QT interval in healthy subjects.

Gopi Krishna Panicker; Deepak Manohar; Dilip R. Karnad; Vaibhav Salvi; Snehal Kothari; Yash Lokhandwala

BACKGROUND An early repolarization (ER) pattern is common in ECGs from patients with ventricular fibrillation (VF). These patients with ER have shorter QT intervals. Morphological variants of the ER pattern also have been associated with idiopathic VF, but their prevalence in healthy subjects is unclear. OBJECTIVE The purpose of this study was to study the prevalence of ER and its morphological variants, and its association with the QTc interval in healthy subjects. METHODS Digital ECGs from 1886 healthy subjects from Phase I clinical trials were analyzed by a central ECG laboratory. RESULTS ER, defined as J-point elevation ≥0.1 mV in ≥2 contiguous leads, was present in 514 subjects (27.3%), of whom 505 (98.2%) were males. The prevalence of ER declined progressively with increasing age. ER pattern was seen in lateral leads (I, aVL, V(4)-V(6)) in 26.1%, in inferior (II, III, aVF) or inferolateral leads in 8%, and was global in 1.9%. The terminal portion of the QRS complex was notched in 43.1% and slurred in 56.9%. Notching was common in inferior/lateral leads, and slurring was common in anterior leads. A non-ascending ST segment was seen in 71% of ECGs with a notched pattern but in only 12.3% of ECGs with a slurred pattern. The ER group had slower heart rates (9.3 ± 13.3 bpm [mean difference ± SD], P <.001) and shorter QTc intervals (QTcB = 20.2 ± 25.6 ms, QTcF = 11.0 ± 21.9 ms; P <.001). Four subjects in each group had a short QT interval (QTcF <350 ms). CONCLUSION ER and all of its variants are common in healthy young males with slower heart rates and slightly shorter QTc intervals. A short QT interval (QTcF <350 ms) is rare.


Annals of Noninvasive Electrocardiology | 2009

Z-score for benchmarking reader competence in a central ECG laboratory.

Gopi Krishna Panicker; Dilip R. Karnad; Rajesh Joshi; Sheetal Shetty; Niraj Vyas; Snehal Kothari; Dhiraj Narula

Background: ECGs from thorough QT studies must be read in a central laboratory by trained experts. Standards of expertise are not presently defined. We, therefore, studied the use of Z‐scores to define reader competence.


Journal of Electrocardiology | 2014

Drug-induced QT prolongation when QT interval is measured in each of the 12 ECG leads in men and women in a thorough QT study

Gopi Krishna Panicker; Vaibhav Salvi; Dilip R. Karnad; Saikat Chakraborty; Deepak Manohar; Yash Lokhandwala; Snehal Kothari

Lead II is commonly used to study drug-induced QT prolongation. Whether other ECG leads too show comparable QT prolongation is not known. We studied moxifloxacin-induced QT prolongation in a thorough QT study in healthy subjects (54 males, 43 females). Placebo-subtracted change from baseline in QTc corrected by Fridericias method (ΔΔQTcF) at 1, 1.5, 2 and 4 hours after moxifloxacin was studied in all 12 leads. Unacceptably wide 90% confidence interval (CI) for ΔΔQTcF was seen in three leads; these leads also had maximum ECGs with flat T waves (60% in aVL, 45% in lead III and 42% in V1). After excluding ECGs with flat T waves, 90% lower CI of ΔΔQTcF was ≥ 5 ms in all leads except leads III, aVL and V1 in men. The 90% lower CI exceeded 5 ms in these leads in women despite wide 90% CIs because of greater mean ΔΔQTcF. Leads III, aVL and V1 should be avoided when measuring QT interval in thorough QT studies.


British Journal of Pharmacology | 2016

Detecting moxifloxacin‐induced QTc prolongation in thorough QT and early clinical phase studies using a highly automated ECG analysis approach

Gopi Krishna Panicker; Dilip R. Karnad; Pramod Kadam; Fabio Badilini; Anil Damle; Snehal Kothari

Exposure–response (ER) modelling (concentration–QTc analysis) is gaining as much acceptance as the traditional by‐time analysis of the placebo‐adjusted change from baseline in the QTc interval (ΔΔQTcF). It has been postulated that intensive ECG analysis and ER modelling during early‐phase drug development could be a cost‐effective approach of estimating QT liability of a new drug, in a small number of subjects.


Journal of Electrocardiology | 2012

Semiautomated QT interval measurement in electrocardiograms from a thorough QT study: comparison of the grouped and ungrouped superimposed median beat methods

Pooja Hingorani; Dilip R. Karnad; Arumugam Ramasamy; Gopi Krishna Panicker; Vaibhav Salvi; Hemant Bhoir; Snehal Kothari

INTRODUCTION We postulated that it may be easier to identify earliest Q onset and latest T offset when the median beats from 12 leads are separated vertically by 5 to 10 mm (ungrouped superimposed median beat [SMB] method) rather than when their baselines closely (but rarely perfectly) overlap (grouped SMB method). METHODS Three readers manually adjudicated annotations placed by an automated algorithm, using grouped (gSMB) and ungrouped (uSMB) methods in 2658 electrocardiograms (ECGs) recorded in 38 subjects in a crossover design thorough QT study at predose and 6 time points postdosing with placebo or moxifloxacin. RESULTS Placebo-subtracted, moxifloxacin-induced QTcF prolongation was comparable with both methods. Maximum QTcF prolongation was seen at 2 hours--10.5 milliseconds (90% confidence interval, 7.9-13.1 milliseconds) with gSMB and 12.9 milliseconds (90% confidence interval, 9.9-15.8 milliseconds) by uSMB. Both methods showed good agreement; mean QT was 4 milliseconds greater by uSMB. Interreader variability of absolute differences in QT measurements was 1 millisecond lower with the uSMB method (6.8 ± 5.7 milliseconds by gSMB and 5.9 ± 4.5 milliseconds by uSMB). CONCLUSION Mean QT was 4 milliseconds longer, and interreader variability, 1 millisecond lower with uSMB. Otherwise, both methods were comparable and detected the moxifloxacin effect.


Journal of Electrocardiology | 2008

Differences between QT and RR intervals in digital and digitized paper electrocardiograms: contribution of the printer, scanner, and digitization process

Pooja Hingorani; Dilip R. Karnad; Gopi Krishna Panicker; Sheetal Deshmukh; Snehal Kothari; Dhiraj Narula

BACKGROUND Prints of electrocardiograms (ECGs) are often sent to core laboratories, where they are scanned, converted to a digital format, and read on-screen. These ECGs may differ from the original ECG because of variability introduced by the printer, scanner, or digitization software. METHODS Digital ECGs were recorded in 50 volunteers simultaneously using electrocardiographs from 2 different manufacturers. QT and RR intervals were measured on-screen on the digitized ECGs. To study the contribution of individual steps in the digitization process, differences in RR interval between 2 prints each of 50 digital ECGs, 2 scanned files of 50 prints, 2 digitized files from 50 scanned files, and 2 readings of 50 digitized ECGs (intrareader variability) were analyzed. RESULTS Repeatability coefficient for RR interval measurement was 18.5 milliseconds for machine 1 and 21 milliseconds for machine 2. Contributions of the printer were 6.5 milliseconds for machine 1 and 9.0 milliseconds for machine 2, digitization process was 5.5 milliseconds, and reader variability was 8.0 milliseconds. Variability of the scanner was negligible. CONCLUSIONS The printer and digitization process account for significant differences in interval measurements in digitized ECGs.

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Yash Lokhandwala

King Edward Memorial Hospital

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Yash Lokhandwala

King Edward Memorial Hospital

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