A pharmacokinetic-pharmacodynamic model for the quantitative prediction of dofetilide clinical QT prolongation from human ether-a-go-go-related gene current inhibition data

Jonker, Daniël M.; Kenna, Leslie A.; Leishman, Derek J.; Wallis, Rob; Milligan, Peter A.; Jonsson, E. Niclas

doi:10.1016/j.clpt.2005.02.004

Cited by 75 publications

(72 citation statements)

References 28 publications

(35 reference statements)

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“…For each antibiotic studied, hERG current inhibition was measured (n ϭ 4 -5 cells) at concentrations ranging from 10 to 300 M. Drugs were perfused in the experimental chamber in a cumulative manner, and dose-response relationships were determined by fitting the data with a Hill equation to obtain inhibitory concentration values of 20 and 50% (IC 20 and IC 50 ). Although hERG IC 50 values are traditionally used for comparison of data, previous studies by our group (Fossa et al, 2004) and others (Redfern et al, 2003;Jonker et al, 2005) have shown that clinically significant prolongation of the QT interval is generally associated with inhibition of hERG current amplitude ranging from 10 to 20%. The IC 20 and IC 50 values determined for the three antibiotics studied were moxifloxacin, 31 and 102 M, erythromycin, 21 and 96 M, and telithromycin, 11 and 46 M, respectively.…”

Section: Resultsmentioning

confidence: 99%

Differentiation of Arrhythmia Risk of the Antibacterials Moxifloxacin, Erythromycin, and Telithromycin Based on Analysis of Monophasic Action Potential Duration Alternans and Cardiac Instability

Wisialowski

Crimin²,

Engtrakul³

et al. 2006

J Pharmacol Exp Ther

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Antibacterial drugs are known to have varying degrees of cardiovascular liability associated with QT prolongation that can lead to the ventricular arrhythmia torsade de pointes. The purpose of these studies was to compare the assessment for the arrhythmogenic risk of moxifloxacin, erythromycin, and telithromycin. Each drug caused dose-dependent inhibition of the rapidly activating delayed rectifier potassium current encoded by the human ether-á -go-go-related gene (hERG) with IC 20 concentrations of 31 M (moxifloxacin), 21 M (erythromycin), and 11 M (telithromycin). These drugs were also evaluated in an anesthetized guinea pig model to measure changes in monophasic action potential duration (MAPD) and to quantify beat-to-beat alternations in MAPD during rapid ventricular pacing. Moxifloxacin dose dependently increased MAPD and caused a rate-dependent increase in alternans at the highest achieved free drug concentration (41 M). Erythromycin also increased MAPD at its highest free drug concentration (58 M), but alternans occurred at a relatively lower therapeutic multiple (13.9 M), and the magnitude of alternans at higher concentrations was independent of pacing rate. Further analysis of the data showed that the beat-to-beat pattern of alternans with erythromycin was less stable than that with moxifloxacin and suggestive of greater arrhythmogenic liability. In contrast to erythromycin and moxifloxacin, telithromycin decreased both MAPD and alternans at the highest achievable drug concentration (7.9 M). The relative risk at therapeutic concentrations is erythromycin Ͼ moxifloxacin Ͼ telithromycin and appears to be consistent with clinical observations of torsade de pointes in patients.

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Section: Resultsmentioning

confidence: 99%

Differentiation of Arrhythmia Risk of the Antibacterials Moxifloxacin, Erythromycin, and Telithromycin Based on Analysis of Monophasic Action Potential Duration Alternans and Cardiac Instability

Wisialowski

Crimin²,

Engtrakul³

et al. 2006

J Pharmacol Exp Ther

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“…It should, however, be acknowledged that QT prolongation is found in humans at estimated free concentrations of PQP which are 10 times lower (0.008 M) than those which block 50% of hERG activity in vitro (0.087 M). A possible explanation for this discrepancy is that QT prolongation in vivo may occur at levels of hERG blockade in the 10% range (23).…”

Section: Discussionmentioning

confidence: 99%

In Vitro Cardiovascular Effects of Dihydroartemisin-Piperaquine Combination Compared with Other Antimalarials

Borsini

Crumb²,

Pace

et al. 2012

Antimicrob Agents Chemother

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The in vitro cardiac properties of dihydroartemisinin (DHA) plus piperaquine phosphate (PQP) were compared with those of other antimalarial compounds. Results with antimalarial drugs, chosen on the basis of their free therapeutic maximum concentration in plasma (C max ), were expressed as the fold of that particular effect with respect to their C max . The following tests were used at 37°C: hERG (human ether-à-go-go-related gene) blockade and trafficking, rabbit heart ventricular preparations, and sodium and slow potassium ion current interference (I Na and I Ks , respectively). Chloroquine, halofantrine, mefloquine, and lumefantrine were tested in the hERG studies, but only chloroquine, dofetilide, lumefantrine, and the combination of artemetherlumefantrine were used in the rabbit heart ventricular preparations, hERG trafficking studies, and I Na and I Ks analyses. A proper reference was used in each test. In hERG studies, the high 50% inhibitory concentration (IC 50 ) of halofantrine, which was lower than its C max , was confirmed. All the other compounds blocked hERG, with IC 50 s ranging from 3-to 30-fold their C max s. In hERG trafficking studies, the facilitative effects of chloroquine at about 30-fold its C max were confirmed and DHA blocked it at a concentration about 300-fold its C max . In rabbit heart ventricular preparations, dofetilide, used as a positive control, revealed a high risk of torsades de pointes, whereas chloroquine showed a medium risk. Neither DHA-PQP nor artemether-lumefantrine displayed an in vitro signal for a significant proarrhythmic risk. Only chloroquine blocked the I Na ion current and did so at about 30-fold its C max . No effect on I Ks was detected. In conclusion, despite significant hERG blockade, DHA-PQP and artemether-lumefantrine do not appear to induce potential torsadogenic effects in vitro, affect hERG trafficking, or block sodium and slow potassium ion currents.

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“…First, the inhibition of the potassium current I inhib ij relative to the i-th cell and the j-th observation was modelled according to [39], that is…”

Section: In Vitro Analysis Herg Current Inhibitionmentioning

confidence: 99%

“…Therefore, besides the assessment of the relationship between dogs and humans in terms of QTinterval prolongation via the development of a population PK/PD model, an operational PK/PD model of pharmacological agonism [38,39] is implemented in order to evaluate the possible connection between the percent inhibition of the human ether-a-go-go-related gene (hERG) and the increase in the QT interval. In particular, in preclinical studies, the hERG assay is widely used to assess the drug effect on the inhibition of the current through the potassium channels (IKr) in cardiac cells.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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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A pharmacokinetic-pharmacodynamic model for the quantitative prediction of dofetilide clinical QT prolongation from human ether-a-go-go-related gene current inhibition data

Cited by 75 publications

References 28 publications

Differentiation of Arrhythmia Risk of the Antibacterials Moxifloxacin, Erythromycin, and Telithromycin Based on Analysis of Monophasic Action Potential Duration Alternans and Cardiac Instability

Differentiation of Arrhythmia Risk of the Antibacterials Moxifloxacin, Erythromycin, and Telithromycin Based on Analysis of Monophasic Action Potential Duration Alternans and Cardiac Instability

In Vitro Cardiovascular Effects of Dihydroartemisin-Piperaquine Combination Compared with Other Antimalarials

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

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