title: Application of a systems pharmacology model for translational prediction of hERG-mediated QTc prolongation.
abstract: Drug-induced QTc interval prolongation (ΔQTc) is a main surrogate for proarrhythmic risk assessment. A higher in vivo than in vitro potency for hERG-mediated QTc prolongation has been suggested. Also, in vivo between-species and patient populations' sensitivity to drug-induced QTc prolongation seems to differ. Here, a systems pharmacology model integrating preclinical in vitro (hERG binding) and in vivo (conscious dogΔQTc) data of three hERG blockers (dofetilide, sotalol, moxifloxacin) was applied (1) to compare the operational efficacy of the three drugs in vivo and (2) to quantify dog-human differences in sensitivity to drug-induced QTc prolongation (for dofetilide only). Scaling parameters for translational in vivo extrapolation of drug effects were derived based on the assumption of system-specific myocardial ion channel densities and transduction of ion channel block: the operational efficacy (transduction of hERG block) in dogs was drug specific (1-19% hERG block corresponded to ≥10 msecΔQTc). System-specific maximal achievableΔQTc was estimated to 28% from baseline in both dog and human, while %hERG block leading to half-maximal effects was 58% lower in human, suggesting a higher contribution of hERG-mediated potassium current to cardiac repolarization. These results suggest that differences in sensitivity to drug-induced QTc prolongation may be well explained by drug- and system-specific differences in operational efficacy (transduction of hERG block), consistent with experimental reports. The proposed scaling approach may thus assist the translational risk assessment of QTc prolongation in different species and patient populations, if mediated by the hERG channel.
authors.affiliation: Systems Pharmacology Leiden Academic Centre for Drug Research (LACDR) Leiden University Leiden The Netherlands; Pediatric Pharmacology and Pharmacometrics University of Basel Children's Hospital (UKBB) Basel Switzerland.
authors.forename: Verena
authors.initials: V
authors.lastname: Gotta
authors.affiliation: Division of Medicinal Chemistry Leiden Academic Centre for Drug Research (LACDR) Leiden University Leiden The Netherlands.
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Global Safety Pharmacology Janssen Research & Development Janssen Pharmaceutica NV Beerse Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Cools
authors.affiliation: Global Safety Pharmacology Janssen Research & Development Janssen Pharmaceutica NV Beerse Belgium.
authors.forename: Karel
authors.initials: K
authors.lastname: van Ammel
authors.affiliation: Global Safety Pharmacology Janssen Research & Development Janssen Pharmaceutica NV Beerse Belgium.
authors.forename: David J
authors.initials: DJ
authors.lastname: Gallacher
authors.affiliation: Quantitative Pharmacology and Pharmacometrics/Merck Research Laboratories Merck & Co., Inc. Upper Gwynedd Pennsylvania.
authors.forename: Sandra A G
authors.initials: SA
authors.lastname: Visser
authors.affiliation: SALAR-Safety and Exploratory Pharmacology Department/Merck Research Laboratories Merck & Co., Inc. West Point Pennsylvania.
authors.forename: Frederick
authors.initials: F
authors.lastname: Sannajust
authors.affiliation: SALAR-Safety and Exploratory Pharmacology Department/Merck Research Laboratories Merck & Co., Inc. West Point Pennsylvania.
authors.forename: Pierre
authors.initials: P
authors.lastname: Morissette
authors.affiliation: Systems Pharmacology Leiden Academic Centre for Drug Research (LACDR) Leiden University Leiden The Netherlands.
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.affiliation: Systems Pharmacology Leiden Academic Centre for Drug Research (LACDR) Leiden University Leiden The Netherlands; Certara Quantitative Systems Pharmacology Canterbury United Kingdom.
authors.forename: Piet H
authors.initials: PH
authors.lastname: van der Graaf
keywords: Drug safety biomarkers; QTc interval; in vitro–in vivo correlation; mechanistic pharmacodynamic modeling; translational research