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Interaction Between Domperidone and Ketoconazole: Toward Prediction of Consequent QTc Prolongation Using Purely In Vitro Information.

Mishra H, Polak S, Jamei M, Rostami-Hodjegan A - CPT Pharmacometrics Syst Pharmacol (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield, UK.

ABSTRACT
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.

No MeSH data available.


Concentration–ΔQTcF relation. Relation between plasma domperidone (a,b) and ketoconazole (c,d) concentration and difference in QTcF from baseline (ΔQTcF), in men (a,c) and women (b,d) on single and combination therapy at steady state (day 7 of dosing). Domperidone alone (empty squares); domperidone in combination (black squares); ketoconazole alone (empty circles); ketoconazole in combination (black circles).
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fig5: Concentration–ΔQTcF relation. Relation between plasma domperidone (a,b) and ketoconazole (c,d) concentration and difference in QTcF from baseline (ΔQTcF), in men (a,c) and women (b,d) on single and combination therapy at steady state (day 7 of dosing). Domperidone alone (empty squares); domperidone in combination (black squares); ketoconazole alone (empty circles); ketoconazole in combination (black circles).

Mentions: Predicted individual ΔQTc values calculated as the individual difference between baseline QTcF and QTcF derived from the simulated ECG signal after the drugs ingestion are presented in Figure 5.


Interaction Between Domperidone and Ketoconazole: Toward Prediction of Consequent QTc Prolongation Using Purely In Vitro Information.

Mishra H, Polak S, Jamei M, Rostami-Hodjegan A - CPT Pharmacometrics Syst Pharmacol (2014)

Concentration–ΔQTcF relation. Relation between plasma domperidone (a,b) and ketoconazole (c,d) concentration and difference in QTcF from baseline (ΔQTcF), in men (a,c) and women (b,d) on single and combination therapy at steady state (day 7 of dosing). Domperidone alone (empty squares); domperidone in combination (black squares); ketoconazole alone (empty circles); ketoconazole in combination (black circles).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150924&req=5

fig5: Concentration–ΔQTcF relation. Relation between plasma domperidone (a,b) and ketoconazole (c,d) concentration and difference in QTcF from baseline (ΔQTcF), in men (a,c) and women (b,d) on single and combination therapy at steady state (day 7 of dosing). Domperidone alone (empty squares); domperidone in combination (black squares); ketoconazole alone (empty circles); ketoconazole in combination (black circles).
Mentions: Predicted individual ΔQTc values calculated as the individual difference between baseline QTcF and QTcF derived from the simulated ECG signal after the drugs ingestion are presented in Figure 5.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield, UK.

ABSTRACT
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.

No MeSH data available.