Inter‐study variability of preclinical <i>in vivo</i> safety studies and translational exposure–<scp>QTc</scp> relationships – a <scp>PKPD</scp> meta‐analysis

Gotta, Verena; Cools, Frank; Ammel, Karel Van; Gallacher, David J.; Visser, Sandra A.G.; Sannajust, Frederick; Morissette, Pierre; Danhof, Meindert; Graaf, Piet H. van der

doi:10.1111/bph.13218

Cited by 14 publications

(34 citation statements)

References 41 publications

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“…In turn, the analysis herein proposed suggests that, for example, the 2.5 % change in the QT interval is equivalent to a median of 10 and 5.85 ms QT-interval prolongation in humans and dogs, respectively. Furthermore, the findings of our analysis are also in agreement with a recently proposed study in which, based on a PK/PD meta-analysis approach, it was found that moxifloxacin concentrations between 2.9 and 5.6 lM induced a typical 4-12 ms prolongation in dogs with a corresponding typical 7-19 ms prolongation in humans [26].…”

Section: Discussionsupporting

confidence: 92%

“…More specifically, in [23] it is mentioned that no cases of TdP in 14,044 patients treated with moxifloxacin were reported. Previous publications [24][25][26] have shown that a model-based paradigm can provide the basis for a translational approach across species. In view of this, preclinical findings as well as the knowledge of the translational relationship between species (e.g.…”

Section: Introductionmentioning

confidence: 99%

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Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities

Marostica

Ammel²,

Teisman³

et al. 2015

J Pharmacokinet Pharmacodyn

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Safety pharmacology studies are performed to assess whether compounds may provoke severe arrhythmias (e.g. Torsades de Pointes, TdP) and sudden death in man. Although there is strong evidence that drugs inducing TdP in man prolong the QT interval in vivo and block the human ether-a-go-go-related gene (hERG) ion channel in vitro, not all drugs affecting the QT interval or the hERG will induce TdP. Nevertheless, QT-interval prolongation and hERG blockade currently represent the most accepted early risk biomarkers to deselect drugs. An extensive pharmacokinetic/pharmacodynamic (PK/PD) analysis is developed to understand moxifloxacin's-induced effects on the QT interval by comparing the relationship between results of an in vitro patch-clamp model to in vivo models. The frequentist and the fully Bayesian estimation procedures were compared and provided similar performances when the best model selected in NONMEM is subsequently implemented in WinBUGS, which guarantees a straightforward calculation of the probability of QT-interval prolongation greater than 2.5 % (10 ms). The use of the percent threshold to account for the intrinsic differences between species and a new calculation of the probability curve are introduced. The concentration providing the 50 % probability indicates that dogs are more sensitive than humans to QT-interval prolongation. However, based on the drug effect, a clear distinction between species cannot be made. An operational PK/PD model of agonism was used to investigate the relationship between effects on the hERG and QT-interval prolongation in dogs. The proposed analysis contributes to establish a translational relationship that could potentially reduce the need for thorough QT studies.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities

Marostica

Ammel²,

Teisman³

et al. 2015

J Pharmacokinet Pharmacodyn

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show abstract

“…Those “system‐ and drug‐specific” translational predictions were externally evaluated using literature data, and compared with “empirical” predictions (from in vivo data alone) (Gotta et al. ) and in silico predictions (from in vitro data alone) (O'Hara et al. ; Mirams et al.…”

Section: Methodsmentioning

confidence: 99%

“…QTc was both in preclinical (Gotta et al. ) and clinical (Jonker et al. ) studies centered to a heart rate of 60 bpm (RR interval of 1000 msec).…”

Section: Methodsmentioning

confidence: 99%

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

Gotta

Cools

et al. 2016

Pharmacol Res Perspect

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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.

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The New S7B/E14 Q&A Document Provides Additional Opportunities to Replace the Thorough QT Study

Darpö¹,

Leishman

2023

The Journal of Clinical Pharma

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Since 2015, concentration–QTc (C–QTc) analysis has been used to exclude the possibility that a drug has a concerning effect on the QTc interval. This has enabled the replacement of the designated thorough QT (TQT) study with serial electrocardiograms (ECGs) in routine clinical pharmacology studies, such as the first‐in‐human (FIH) study. The E14 revision has led to an increased proportion of FIH studies with the added objective of QT evaluation, with the intention of replacing the TQT study. With the more recent revision of the S7B/E14 Q&A document in February 2022, nonclinical assays/studies can be brought into the process of regulatory decisions at the time of marketing application. If the hERG (human ether‐a‐go‐go‐related gene) and the non‐rodent in vivo study are conducted according to the described best practices and are negative, the previous requirement that a QTc effect of >10 milliseconds must be excluded in healthy subjects at plasma concentrations 2‐fold above what can be seen in patients can be reduced to covering the concentrations seen in patients. For drugs that cannot be safely given in high doses to healthy subjects, ECG evaluation is often performed at the therapeutic dose in patients. If a QTc effect of >10 milliseconds can be excluded, an argument can be made that the drug should be considered as having a low likelihood of proarrhythmic effects due to delayedrepolarization, if supported by negative best practices hERG and in vivo studies. In this article, we describe what clinicians involved in early clinical development need to understand in terms of the hERG and in vivo studies to determine whether these meet best practices and therefore can be used in an integrated clinical/nonclinical QT/QTc risk assessment.

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Inter‐study variability of preclinical in vivo safety studies and translational exposure–QTc relationships – a PKPD meta‐analysis

Cited by 14 publications

References 41 publications

Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities

Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities

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

The New S7B/E14 Q&A Document Provides Additional Opportunities to Replace the Thorough QT Study

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