Application of a systems pharmacology model for translational prediction of hERG ‐mediated QT c prolongation

Abstract

Drug‐induced QTc interval prolongation (Δ QTc) 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 dog Δ QTc) 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 msec Δ QTc). System‐specific maximal achievable Δ QTc 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.

Quantitative systems pharmacology analysis of drug combination and scaling to humans: the interaction between noradrenaline and vasopressin in vasoconstriction

“…and V 1A receptors could be further investigated. The applicability of such a system-pharmacology approach to explaining differences between hERG-mediated QTC prolongation in adults and neonates on the basis of modelpredicted differences in target expression levels, which were consistent with experimentally derived mRNA levels in patients (Moric-Janiszewska et al, 2011), has been recently demonstrated (Gotta et al, 2016).…”

An Integrative Approach for Improved Assessment of Cardiovascular Safety Data

“…The majority of these neglect the intertwined dependencies across cardiovascular measures, making comparison of results difficult. For instance, gamma parameters in Tables 4 and 5 were generally lower than previously reported values in human (Chu et al, 1999;Duffull et al, 2000;Mehrotra et al, 2007;Gotta et al, 2016), generally reported to be ≥1, but it is unclear whether this stems from differences in species or model. A few studies (Francheteau et al, 1993;Upton and Ludbrook, 2005;Snelder et al, 2014;Kamendi et al, 2016) have applied an integrative approach including inter-relationships between TPR, SV, and MAP.…”

Bundling arrows: improving translational CNS drug development by integrated PK/PD-metabolomics

“…A recent evaluation of a Transient Receptor Potential Melastatin-8 blocker showed threefold cross-species (mouse versus dog) differences in its potency, resulting in clinically important differences in core body temperature predictions [57]. In another study, the E max and EC 50 for prolonging the QT-interval were found to differ between humans and dogs [58]. A third publication showed that the affinity of psychoactive drugs differed significantly between, for example, the D1 rat and 5HT2 rat , and D1 human and 5HT2 human receptors [9].…”