A pharmacokinetic-pharmacodynamic model for the quantitative prediction of dofetilide clinical QT prolongation from human ether-a-go-go-related gene current inhibition data.
BACKGROUND
QT prolongation is an important biomarker of the arrhythmia torsades de pointes and appears to be related mainly to blockade of delayed inward cardiac rectifier potassium currents. The aim of this study was to quantify the relationship between in vitro human ether-a-go-go-related gene (hERG) potassium channel blockade and the magnitude of QT prolongation in humans for the class III antiarrhythmic dofetilide.


METHODS
The in vitro affinity and activity of dofetilide were determined in recombinant cell cultures expressing the hERG channel, and the QT-prolonging effect of dofetilide was assessed in 5 clinical studies (80 healthy volunteers and 17 patients with ischemic heart disease). A population pharmacokinetic-pharmacodynamic analysis of the in vitro and in vivo data was performed in NONMEM by use of the operational model of pharmacologic agonism to estimate the efficiency of transduction from ion channel binding to Fridericia-corrected QT response.


RESULTS
A 3-compartment pharmacokinetic model with first-order absorption characterized the time course of dofetilide concentrations. On the basis of an in vitro potency of 5.13 ng/mL for potassium current inhibition and predicted unbound dofetilide concentrations, the estimated transducer ratio (tau) of 6.2 suggests that the QT response plateaus before currents are fully blocked. In our study population, 10% hERG blockade corresponds to a QT prolongation of 20 ms (95% confidence interval, 12-32 ms). With long-term dofetilide administration, tolerance develops with a half-life of 4.7 days.


CONCLUSIONS
The current mechanism-based pharmacokinetic-pharmacodynamic model quantified the relationship between in vitro hERG channel blockade and clinical QT prolongation for dofetilide. This model may prove valuable for assessing the risk of QT prolongation in humans for other drugs that selectively block the hERG channel on the basis of in vitro assays and pharmacokinetic properties.
Jonker
Daniël M
DM
Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Faculty of Pharmacy, Uppsala University, Sweden. daniel.jonker@farmbio.uu.se
Kenna
Leslie A
LA
Leishman
Derek
D
Wallis
Rob
R
Milligan
Peter A
PA
Jonsson
E Niclas
EN
D000293:Adolescent; D000328:Adult; D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics*; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D018929:Cell Culture Techniques; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D006329:Heart Conduction System / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics / Q000503:physiopathology*; D008875:Middle Aged; D008955:Models, Cardiovascular; D010627:Phenethylamines / Q000493:pharmacokinetics*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000235:genetics*; D013449:Sulfonamides / Q000493:pharmacokinetics*
D000889:Anti-Arrhythmia Agents; D027682:Cation Transport Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D010627:Phenethylamines; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; C063533:dofetilide