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

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 (Delta Delta QTcF) 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-Delta Delta QTcF hysteresis, and the influence of vomiting. Nonlinear mixed-effects modeling was applied to characterize pharmacokinetics and pharmacodynamics, i.e., Delta Delta QTcF. Simulations were used to predict Delta Delta QTcF for expected therapeutic dose used in Phase 3 clinical development. Correction for RR-QT hysteresis did not influence Delta Delta QTcF 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 Delta Delta QTcF 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.

Automated summary

The potential QT prolongation effect of Clazosentan was investigated through a thorough QT study, revealing a delayed effect associated with vomiting. Nonlinear mixed-effects modeling was used to characterize the concentration-QT relationship considering hysteresis, with pharmacokinetics best described by a linear two-compartment model. Despite apparent differences between subjects with and without vomiting, vomiting did not have a statistically significant influence on QT prolongation.