Single Doses up to 800 mg of E-52862 Do Not Prolong the QTc Interval – A Retrospective Validation by Pharmacokinetic-Pharmacodynamic Modelling of Electrocardiography Data Utilising the Effects of a Meal on QTc to Demonstrate ECG Assay Sensitivity

Jörg Täubel; Georg Ferber; Ulrike Lorch; Duolao Wang; Mariano Sust; A. John Camm

doi:10.1371/journal.pone.0136369

Single Doses up to 800 mg of E-52862 Do Not Prolong the QTc Interval – A Retrospective Validation by Pharmacokinetic-Pharmacodynamic Modelling of Electrocardiography Data Utilising the Effects of a Meal on QTc to Demonstrate ECG Assay Sensitivity

Jörg Täubel, Georg Ferber, Ulrike Lorch, Duolao Wang, Mariano Sust, A. John Camm

Clinical Sciences

Research output: Contribution to journal › Article › peer-review

15 Citations (Scopus)

Abstract

Background

E-52862 is a Sigma-1 receptor antagonist (S1RA) currently under investigation as a potential analgesic medicine. We successfully applied a concentration-effect model retrospectively to a four-way crossover Phase I single ascending dose study and utilized the QTc shortening effects of a meal to demonstrate assay sensitivity by establishing the time course effects from baseline in all four periods, independently from any potential drug effects.

Methods

Thirty two healthy male and female subjects were included in four treatment periods to receive single ascending doses of 500 mg, 600 mg or 800 mg of E-52862 or placebo. PK was linear over the dose range investigated and doses up to 600 mg were well tolerated. The baseline electrocardiography (ECG) measurements on Day-1 were time-matched with ECG and pharmacokinetic (PK) samples on Day 1 (dosing day).

Results

In this conventional mean change to time-matched placebo analysis, the largest time-matched difference to placebo QTcI was 1.44 ms (90% CI: -4.04, 6.93 ms) for 500 mg; -0.39 ms (90% CI: -3.91, 3.13 ms) for 600 mg and 1.32 ms (90% CI: -1.89, 4.53 ms) for 800 mg of E-52862, thereby showing the absence of any QTc prolonging effect at the doses tested. In addition concentration-effect models, one based on the placebo corrected change from baseline and one for the change of QTcI from average baseline with time as fixed effect were fitted to the data confirming the results of the time course analysis.

Conclusion

The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a shortening of QTcF of -8.1 (90% CI: -10.4, -5.9) one hour and -7.2 (90% CI: -9.4, -5.0) three hours after a standardised meal.

Trial Registration

EU Clinical Trials Register EudraCT 2010 020343 13

Original language	English
Article number	e0136369
Pages (from-to)	e0136369
Journal	PLoS ONE
Volume	10
Issue number	8
DOIs	https://doi.org/10.1371/journal.pone.0136369
Publication status	Published - 20 Aug 2015

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Täubel, J., Ferber, G., Lorch, U., Wang, D., Sust, M., & Camm, A. J. (2015). Single Doses up to 800 mg of E-52862 Do Not Prolong the QTc Interval – A Retrospective Validation by Pharmacokinetic-Pharmacodynamic Modelling of Electrocardiography Data Utilising the Effects of a Meal on QTc to Demonstrate ECG Assay Sensitivity. PLoS ONE, 10(8), e0136369. Article e0136369. https://doi.org/10.1371/journal.pone.0136369

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title = "Single Doses up to 800 mg of E-52862 Do Not Prolong the QTc Interval – A Retrospective Validation by Pharmacokinetic-Pharmacodynamic Modelling of Electrocardiography Data Utilising the Effects of a Meal on QTc to Demonstrate ECG Assay Sensitivity",

abstract = "BackgroundE-52862 is a Sigma-1 receptor antagonist (S1RA) currently under investigation as a potential analgesic medicine. We successfully applied a concentration-effect model retrospectively to a four-way crossover Phase I single ascending dose study and utilized the QTc shortening effects of a meal to demonstrate assay sensitivity by establishing the time course effects from baseline in all four periods, independently from any potential drug effects.MethodsThirty two healthy male and female subjects were included in four treatment periods to receive single ascending doses of 500 mg, 600 mg or 800 mg of E-52862 or placebo. PK was linear over the dose range investigated and doses up to 600 mg were well tolerated. The baseline electrocardiography (ECG) measurements on Day-1 were time-matched with ECG and pharmacokinetic (PK) samples on Day 1 (dosing day).ResultsIn this conventional mean change to time-matched placebo analysis, the largest time-matched difference to placebo QTcI was 1.44 ms (90\% CI: -4.04, 6.93 ms) for 500 mg; -0.39 ms (90\% CI: -3.91, 3.13 ms) for 600 mg and 1.32 ms (90\% CI: -1.89, 4.53 ms) for 800 mg of E-52862, thereby showing the absence of any QTc prolonging effect at the doses tested. In addition concentration-effect models, one based on the placebo corrected change from baseline and one for the change of QTcI from average baseline with time as fixed effect were fitted to the data confirming the results of the time course analysis.ConclusionThe sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a shortening of QTcF of -8.1 (90\% CI: -10.4, -5.9) one hour and -7.2 (90\% CI: -9.4, -5.0) three hours after a standardised meal.Trial RegistrationEU Clinical Trials Register EudraCT 2010 020343 13",

author = "J{\"o}rg T{\"a}ubel and Georg Ferber and Ulrike Lorch and Duolao Wang and Mariano Sust and Camm, \{A. John\}",

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Täubel, J, Ferber, G, Lorch, U, Wang, D, Sust, M & Camm, AJ 2015, 'Single Doses up to 800 mg of E-52862 Do Not Prolong the QTc Interval – A Retrospective Validation by Pharmacokinetic-Pharmacodynamic Modelling of Electrocardiography Data Utilising the Effects of a Meal on QTc to Demonstrate ECG Assay Sensitivity', PLoS ONE, vol. 10, no. 8, e0136369, pp. e0136369. https://doi.org/10.1371/journal.pone.0136369

Single Doses up to 800 mg of E-52862 Do Not Prolong the QTc Interval – A Retrospective Validation by Pharmacokinetic-Pharmacodynamic Modelling of Electrocardiography Data Utilising the Effects of a Meal on QTc to Demonstrate ECG Assay Sensitivity. / Täubel, Jörg; Ferber, Georg; Lorch, Ulrike et al.
In: PLoS ONE, Vol. 10, No. 8, e0136369, 20.08.2015, p. e0136369.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Single Doses up to 800 mg of E-52862 Do Not Prolong the QTc Interval – A Retrospective Validation by Pharmacokinetic-Pharmacodynamic Modelling of Electrocardiography Data Utilising the Effects of a Meal on QTc to Demonstrate ECG Assay Sensitivity

AU - Täubel, Jörg

AU - Ferber, Georg

AU - Lorch, Ulrike

AU - Wang, Duolao

AU - Sust, Mariano

AU - Camm, A. John

PY - 2015/8/20

Y1 - 2015/8/20

N2 - BackgroundE-52862 is a Sigma-1 receptor antagonist (S1RA) currently under investigation as a potential analgesic medicine. We successfully applied a concentration-effect model retrospectively to a four-way crossover Phase I single ascending dose study and utilized the QTc shortening effects of a meal to demonstrate assay sensitivity by establishing the time course effects from baseline in all four periods, independently from any potential drug effects.MethodsThirty two healthy male and female subjects were included in four treatment periods to receive single ascending doses of 500 mg, 600 mg or 800 mg of E-52862 or placebo. PK was linear over the dose range investigated and doses up to 600 mg were well tolerated. The baseline electrocardiography (ECG) measurements on Day-1 were time-matched with ECG and pharmacokinetic (PK) samples on Day 1 (dosing day).ResultsIn this conventional mean change to time-matched placebo analysis, the largest time-matched difference to placebo QTcI was 1.44 ms (90% CI: -4.04, 6.93 ms) for 500 mg; -0.39 ms (90% CI: -3.91, 3.13 ms) for 600 mg and 1.32 ms (90% CI: -1.89, 4.53 ms) for 800 mg of E-52862, thereby showing the absence of any QTc prolonging effect at the doses tested. In addition concentration-effect models, one based on the placebo corrected change from baseline and one for the change of QTcI from average baseline with time as fixed effect were fitted to the data confirming the results of the time course analysis.ConclusionThe sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a shortening of QTcF of -8.1 (90% CI: -10.4, -5.9) one hour and -7.2 (90% CI: -9.4, -5.0) three hours after a standardised meal.Trial RegistrationEU Clinical Trials Register EudraCT 2010 020343 13

AB - BackgroundE-52862 is a Sigma-1 receptor antagonist (S1RA) currently under investigation as a potential analgesic medicine. We successfully applied a concentration-effect model retrospectively to a four-way crossover Phase I single ascending dose study and utilized the QTc shortening effects of a meal to demonstrate assay sensitivity by establishing the time course effects from baseline in all four periods, independently from any potential drug effects.MethodsThirty two healthy male and female subjects were included in four treatment periods to receive single ascending doses of 500 mg, 600 mg or 800 mg of E-52862 or placebo. PK was linear over the dose range investigated and doses up to 600 mg were well tolerated. The baseline electrocardiography (ECG) measurements on Day-1 were time-matched with ECG and pharmacokinetic (PK) samples on Day 1 (dosing day).ResultsIn this conventional mean change to time-matched placebo analysis, the largest time-matched difference to placebo QTcI was 1.44 ms (90% CI: -4.04, 6.93 ms) for 500 mg; -0.39 ms (90% CI: -3.91, 3.13 ms) for 600 mg and 1.32 ms (90% CI: -1.89, 4.53 ms) for 800 mg of E-52862, thereby showing the absence of any QTc prolonging effect at the doses tested. In addition concentration-effect models, one based on the placebo corrected change from baseline and one for the change of QTcI from average baseline with time as fixed effect were fitted to the data confirming the results of the time course analysis.ConclusionThe sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a shortening of QTcF of -8.1 (90% CI: -10.4, -5.9) one hour and -7.2 (90% CI: -9.4, -5.0) three hours after a standardised meal.Trial RegistrationEU Clinical Trials Register EudraCT 2010 020343 13

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Täubel J, Ferber G, Lorch U, Wang D, Sust M, Camm AJ. Single Doses up to 800 mg of E-52862 Do Not Prolong the QTc Interval – A Retrospective Validation by Pharmacokinetic-Pharmacodynamic Modelling of Electrocardiography Data Utilising the Effects of a Meal on QTc to Demonstrate ECG Assay Sensitivity. PLoS ONE. 2015 Aug 20;10(8):e0136369. e0136369. doi: 10.1371/journal.pone.0136369