Concentration–Response Modeling of ECG Data From Early‐Phase Clinical Studies as an Alternative Clinical and Regulatory Approach to Assessing QT Risk — Experience From the Development Program of Lemborexant

@article{Murphy2017ConcentrationResponseMO,
  title={Concentration–Response Modeling of ECG Data From Early‐Phase Clinical Studies as an Alternative Clinical and Regulatory Approach to Assessing QT Risk — Experience From the Development Program of Lemborexant},
  author={Patricia Murphy and Sanae Yasuda and Kenya Nakai and Takashi Yoshinaga and Nancy Hall and Meijian Zhou and Jagadeesh Aluri and Bhaskar Rege and Margaret Moline and James J. Ferry and Borje Darpo},
  journal={The Journal of Clinical Pharmacology},
  year={2017},
  volume={57}
}
Lemborexant is a novel dual orexin receptor antagonist being developed to treat insomnia. Its potential to cause QT prolongation was evaluated using plasma concentration–response (CR) modeling applied to data from 2 multiple ascending‐dose (MAD) studies. In the primary MAD study, placebo or lemborexant (2.5 to 75 mg) was administered for 14 consecutive nights. In another MAD study designed to “bridge” pharmacokinetic and safety data between Japanese and non‐Japanese subjects (J‐MAD), placebo or… 
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Retrospective high‐precision QT analysis was performed on serial elecrocardiograms extracted from first‐in‐human single‐ascending dose (SAD) and multiple‐ascends dose (MAD) studies to evaluate if early studies could detect and predict QT effect, and mild QT prolongation observed postdose with a supratherapeutic dose could be detected and estimated in SAD/MAD studies.
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TLDR
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TLDR
Itacitinib is a JAK1‐selective inhibitor in phase 3 development in graft‐versus‐host disease and no clinically meaningful effects on cardiac conduction (PR and QRS intervals) or any categorical PR or QRS outliers were observed.
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TLDR
The upper bound of 90% confidence intervals of the ∆QTcF was below the 10 ms threshold of regulatory concern for all concentrations measured, andpecified sensitivity analysis confirmed the results in both sexes, in those over and below 60 years, and in Japanese subjects.
Study Design Parameters Affecting Exposure Response Analysis of QT Data: Results From Simulation Studies
TLDR
One thousand single‐ascending‐dose SAD studies with 7 dose groups with 6/2 subjects on active drug/placebo were generated through simulation for each of 32 scenarios with 8 different QT effects of the study drug and achieved plasma concentration 2‐ or 4‐fold above therapeutic levels.
Assessing QT/QTc interval prolongation with concentration-QT modeling for Phase I studies: impact of computational platforms, model structures and confidence interval calculation methods
TLDR
It is shown that treatment- and time-specific intercepts may need to be included into C-∆QTc modeling through PROC MIXED or LME4, regardless of their statistical significance, as well as three methods for calculating the confidence interval (CI) of QTc prolongation (analytical and bootstrap methods with fixed or varied geometric mean concentrations).
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References

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  • Medicine
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  • 2014
TLDR
A clinical study in healthy subjects demonstrating that the thorough QT (TQT) study can be replaced by robust ECG monitoring and exposure–response analysis of data generated from First‐in‐Man single ascending dose (SAD) studies is designed.
Results From the IQ‐CSRC Prospective Study Support Replacement of the Thorough QT Study by QT Assessment in the Early Clinical Phase
TLDR
There is evidence that robust QT assessment in early‐phase clinical studies can replace the thorough QT study, and exposure–response analysis can detect QT effects in a small study with healthy subjects.
Operational Characteristics of Linear Concentration‐QT Models for Assessing QTc Interval in the Thorough QT and Phase I Clinical Studies
TLDR
C‐QTc models that incorporate time‐ and treatment‐specific terms give the least biased ΔΔ QTcmax predictions under scenarios of model‐misspecifications and offer an advantage when applying to real clinical data where the underlying relationship is not known.
Implications of the IQ-CSRC Prospective Study: Time to Revise ICH E14
TLDR
Evidence is provided that careful QT assessment in early phase clinical studies can be used as an alternative to the thorough QT study, and clinical and regulatory implications, as well as limitations of this approach are discussed in the commentary.
Early QT assessment – how can our confidence in the data be improved?
TLDR
How QT assessment can be applied to early clinical studies and what is needed to achieve the same high confidence in the data are discussed, and a recent research proposal is described, which may generate data to support the replacement of the TQT study with data from QT Assessment in early phase 1 studies.
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TLDR
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TLDR
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  • Medicine
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TLDR
A prospective study is detailed to test the hypothesis that using PK/QTc modeling in a single ascending dose design study, such as is typically performed in the first-in-human study (FIM), will be sufficiently sensitive to detect QTc effects, to be acceptable in lieu of the thorough QT (TQT) study.
Concentration‐QT Relationships Play a Key Role in the Evaluation of Proarrhythmic Risk During Regulatory Review
TLDR
The authors provide examples to illustrate how the concentration‐QT relationship has been used to plan and interpret the thorough QT study, to evaluate QT risk for drugs that have no thorough Qt studies, to assess QTrisk in subpopulations, to make dose adjustments, and to write informative drug labels.
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  • Biology
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TLDR
Methods and approaches to increase the confidence in ECG data derived from "early QT assessment" in single-ascending/multiple-ascends dose studies are discussed, and a path toward replacing the TQT study using these approaches will be outlined.
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