PKPD and cardiac single cell modeling of a DDI study with a CYP3A4 substrate and itraconazole to quantify the effects on QT interval duration

Abstract

Plasma drug concentration and electrocardiogram (ECG) data from a drug–drug interaction (DDI) study employing the metabolic inhibitor itraconazole have been used as part of a prospectively defined pharmacokinetic/pharmacodynamic modelling strategy to quantify the potential for QT interval prolongation from basmisanil, an investigational compound. ECG data were collected on multiple days during repeat dosing treatment regimens, thereby allowing the capture of QT data across a wide range of drug concentrations in each study participant and encompassing both “therapeutic” and “supra-therapeutic” exposures. The data were used to develop a non-linear mixed effect concentration-QT (C-QT) model that differentiated drug-induced QT prolongation from other factors altering QT interval duration. Food effects were accounted by quantitating their influences on the parameters describing the diurnal variation of QT. The final model demonstrated that itraconazole does not cause QT prolongation, while for basmisanil, the 1-sided upper 95% CI of the QT interval at 240 mg (the highest dose tested in ongoing phase 2 studies) with DDI, was below the 10 ms threshold considered to be of clinical significance by regulatory authorities. The empirical modelling was complemented with a human mechanistic cardiac single cell model that was used to simulate the change in action potential duration as a function of drug concentration. The results of the two approaches were in agreement, suggesting that the effect of basmisanil on QT interval duration can be attributed to the effect on hERG alone. The C-QT model for basmisanil can be used to derive the QT interval corrected changes in heart rate (QTc) and thus inform cardiac safety strategy in later development without the need for a separate, dedicated study.

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Correspondence to Cheikh Diack.

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Jaminion, F., Bentley, D., Wang, K. et al. PKPD and cardiac single cell modeling of a DDI study with a CYP3A4 substrate and itraconazole to quantify the effects on QT interval duration. J Pharmacokinet Pharmacodyn (2020). https://doi.org/10.1007/s10928-020-09696-y

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Keywords

  • Action potential duration
  • Drug–drug interaction
  • Itraconazole
  • Pharmacokinetic
  • Pharmacodynamic
  • QT
  • QTc
  • QTcF