PK/PD Modelling of the QT Interval: a Step Towards Defining the Translational Relationship Between In Vitro, Awake Beagle Dogs, and Humans.
Inhibiting the human ether-a-go-go-related gene (hERG)-encoded potassium ion channel is positively correlated with QT-interval prolongation in vivo, which is considered a risk factor for the occurrence of Torsades de Pointes (TdP). A pharmacokinetic/pharmacodynamic model was developed for four compounds that reached the clinic, to relate drug-induced QT-interval change in awake dogs and humans and to derive a translational scaling factor a 1. Overall, dogs were more sensitive than humans to QT-interval change, an a 1 of 1.5 was found, and a 10% current inhibition in vitro produced a higher percent QT-interval change in dogs as compared to humans. The QT-interval changes in dogs were predictive for humans. In vitro and in vivo information could reliably describe the effects in humans. Robust translational knowledge is likely to reduce the need for expensive thorough QT studies; therefore, expanding this work to more compounds is recommended.
Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium. ele126@hotmail.it.|LAP&P Consultants B.V., Leiden, The Netherlands. ele126@hotmail.it.
Eleonora
E
Marostica
Global Safety Pharmacology, Janssen R&D, Janssen Pharmaceutica NV, Beerse, Belgium.
Karel
K
Van Ammel
Global Safety Pharmacology, Janssen R&D, Janssen Pharmaceutica NV, Beerse, Belgium.
Ard
A
Teisman
Global Safety Pharmacology, Janssen R&D, Janssen Pharmaceutica NV, Beerse, Belgium.
David
D
Gallacher
Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium.
Jan
J
Van Bocxlaer
Statistics & Decision Sciences, Janssen R&D, Janssen Pharmaceutica NV, Beerse, Belgium.
Filip
F
De Ridder
Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium.
Koen
K
Boussery
Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium.|Clinical Pharmacology & Pharmacometrics, Janssen R&D, Janssen Pharmaceutica NV, Beerse, Belgium.
An
A
Vermeulen
D000465:Algorithms; D000818:Animals; D004285:Dogs; D000072237:ERG1 Potassium Channel / Q000037:antagonists & inhibitors*; D004562:Electrocardiography; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D015233:Models, Statistical; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011336:Probability; D012307:Risk Factors; D013045:Species Specificity; D016171:Torsades de Pointes / Q000139:chemically induced; D014851:Wakefulness
D000072237:ERG1 Potassium Channel; D026902:Potassium Channel Blockers
QT-interval change; in vitro awake beagle dogs and humans; in vitro current inhibition; percent critical threshold; translational scaling factor