Key result
Mechanistic PK/PD modeling accurately predicts QTc prolongation from combined domperidone and ketoconazole.
Why the study?
Does coadministration of domperidone and ketoconazole increase QTc prolongation compared to domperidone alone in a simulated healthy population?
Does coadministration of domperidone and ketoconazole increase QTc prolongation compared to domperidone alone in a simulated healthy population?
In silico PBPK-PD modeling can predict drug-drug interaction-induced QTc prolongation, highlighting its potential utility in early cardiac safety assessment.
Supports in silico DDI QTc prediction; leaves open human validation before clinical use.
We aimed to investigate the application of combined mechanistic pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation in predicting the domperidone (DOM) triggered pseudo-electrocardiogram modification in the presence of a CYP3A inhibitor, ketoconazole (KETO), using in vitro-in vivo extrapolation. In vitro metabolic and inhibitory data were incorporated into physiologically based pharmacokinetic (PBPK) models within Simcyp to simulate time course of plasma DOM and KETO concentrations when administered alone or in combination with KETO (DOM+KETO). Simulated DOM concentrations in plasma were used to predict changes in gender-specific QTcF (Fridericia correction) intervals within the Cardiac Safety Simulator platform taking into consideration DOM, KETO, and DOM+KETO triggered inhibition of multiple ionic currents in population. Combination of in vitro-in vivo extrapolation, PBPK, and systems pharmacology of electric currents in the heart was able to predict the direction and magnitude of PK and PD changes under coadministration of the two drugs although some disparities were detected.
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Mishra et al. (2014) studied Healthy virtual volunteers (n=24). Domperidone and Ketoconazole coadministration vs. Domperidone alone or Ketoconazole alone was evaluated on Change in QTcF interval (ΔQTc). Combined mechanistic pharmacokinetic and pharmacodynamic modeling successfully predicted the direction and magnitude of QTc prolongation under coadministration of domperidone and ketoconazole.
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