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

Abstract

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.

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

“…While this stresses the importance of characterizing this low pharmacodynamic range in vitro, it also indicates that predictions from in vitro data alone can be difficult because of drug‐specific intrinsic efficacy: almost identical transducer ratios were estimated for the structurally similar compounds dofetilide and sotalol in dog, while it was 10 times higher for moxifloxacin, consistent with a recent publication (Marostica et al. ). The transducer ratio differences between drugs are supported by experimental data suggesting that the mechanism of moxifloxacin binding in the inner cavity of the hERG channel differs from antiarrhythmic drugs regarding, for example, interaction with specific amino acid residues, state and voltage dependency of hERG block (Thomas et al.…”

Pharmacodynamic modeling of adverse effects of anti-cancer drug treatment

“…Anti-cancer drugs, such as anthracyclines and tyrosine kinase inhibitors, can prolong the QT interval, which can lead to severe cardiac arrhythmias, such as torsade de pointes [ 38 ]. Concentration-QT modeling can provide important information on the relation between exposure and heart rate-corrected QT interval (QTc) [ 43 , 44 ]. However, these models are mainly developed for anti-arrhythmic drugs and not for anti-cancer drugs.…”

“…However, these models are mainly developed for anti-arrhythmic drugs and not for anti-cancer drugs. A recent publication investigated the effect of moxifloxacine, a compound that prolongs the QT interval, by developing a PK-PD model for translational purposes [ 43 ]. The time course of the QT interval is described by the following three components: the individual heart rate correction, the circadian rhythm, and the drug effect: …”