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PK/PD modeling of a clazosentan thorough QT study with hysteresis in concentration-QT and RR-QT

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Abstract

Clazosentan's potential QT liability was investigated in a thorough QT study in which clazosentan was administered intravenously as a continuous infusion of 20 mg/h immediately followed by 60 mg/h. Clazosentan prolonged the placebo-corrected change-from-baseline QT interval corrected for RR with Fridericia's formula (ΔΔQTcF) with the maximum QT effect occurring 4 h after the maximum drug concentration, apparently associated with vomiting. The delayed effect precluded the standard linear modeling approach. This analysis aimed at characterizing the concentration-QT relationship in consideration of RR-QT hysteresis, concentration-ΔΔQTcF hysteresis, and the influence of vomiting. Nonlinear mixed-effects modeling was applied to characterize pharmacokinetics and pharmacodynamics, i.e., ΔΔQTcF. Simulations were used to predict ΔΔQTcF for expected therapeutic dose used in Phase 3 clinical development. Correction for RR-QT hysteresis did not influence ΔΔQTcF to a relevant extent. Pharmacokinetics of clazosentan were best described by a linear two-compartment model. The delayed QT prolongation was characterized by an indirect-response model with loglinear drug effect. Vomiting had no statistically significant influence on QT prolongation despite apparent differences between subjects vomiting and not vomiting, probably since vomiting occurred mostly after the main QT prolongation. Following a simulated 3-h infusion of 15 mg/h of clazosentan, the upper bound of the predicted 90% CI for mean ΔΔQTcF was expected to exceed the 10-ms regulatory threshold of concern with maximum effect 3.5 h after end of infusion. TRN: NCT03657446, 05 Sep 2018.

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Funding

This study was funded by Idorsia Pharmaceuticals Ltd.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland

    Andrea Henrich, Pierre-Eric Juif, Jasper Dingemanse & Andreas Krause

Authors
  1. Andrea Henrich
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  2. Pierre-Eric Juif
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  3. Jasper Dingemanse
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  4. Andreas Krause
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Contributions

All authors contributed to study design, analysis, and interpretation. AH performed the analysis and wrote the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Andreas Krause.

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All authors are employees and shareholders of Idorsia.

Research involving human participants, their data or biological material

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The protocol was approved by the Ethics Committee (Medisch Ethische Toetsings Commissie, Assen, The Netherlands).

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Henrich, A., Juif, PE., Dingemanse, J. et al. PK/PD modeling of a clazosentan thorough QT study with hysteresis in concentration-QT and RR-QT. J Pharmacokinet Pharmacodyn 48, 213–224 (2021). https://doi.org/10.1007/s10928-020-09728-7

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  • DOI: https://doi.org/10.1007/s10928-020-09728-7

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