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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.


Predicted steady-state (day 7) systemic concentration of domperidone (10 simulated trials: grey solid lines; mean profile without inhibitor: black solid line; with inhibitor: black dotted line) superimposed with observed data (without inhibitor: triangles; with inhibitor: circles) in healthy (a) men and (b) women volunteers.
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fig1: Predicted steady-state (day 7) systemic concentration of domperidone (10 simulated trials: grey solid lines; mean profile without inhibitor: black solid line; with inhibitor: black dotted line) superimposed with observed data (without inhibitor: triangles; with inhibitor: circles) in healthy (a) men and (b) women volunteers.

Mentions: The steady-state (day 7) predicted DOM (10 mg, four doses daily, at 4 h intervals) concentration–time profile (Mean ± SD) superimposed with observed data, with and without coadministration of CYP3A inhibitor KETO (200 mg every 12 h), for men and women and KETO alone, is presented in Figures 1 and 2 respectively. A summary of comparison of observed and simulated PK parameters is presented in Table 1.


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)

Predicted steady-state (day 7) systemic concentration of domperidone (10 simulated trials: grey solid lines; mean profile without inhibitor: black solid line; with inhibitor: black dotted line) superimposed with observed data (without inhibitor: triangles; with inhibitor: circles) in healthy (a) men and (b) women volunteers.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Predicted steady-state (day 7) systemic concentration of domperidone (10 simulated trials: grey solid lines; mean profile without inhibitor: black solid line; with inhibitor: black dotted line) superimposed with observed data (without inhibitor: triangles; with inhibitor: circles) in healthy (a) men and (b) women volunteers.
Mentions: The steady-state (day 7) predicted DOM (10 mg, four doses daily, at 4 h intervals) concentration–time profile (Mean ± SD) superimposed with observed data, with and without coadministration of CYP3A inhibitor KETO (200 mg every 12 h), for men and women and KETO alone, is presented in Figures 1 and 2 respectively. A summary of comparison of observed and simulated PK parameters is presented in Table 1.

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.