Predictive model for L‐type channel inhibition: multichannel block in QT prolongation risk assessment

Wiśniowska, Barbara; Mendyk, Aleksander; Fijorek, Kamil; Glinka, Anna; Polak, Sebastian

doi:10.1002/jat.2784

Cited by 15 publications

(13 citation statements)

References 26 publications

(24 reference statements)

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“…TdP classified antidepressants have different potencies to block hERG channels at clinically relevant concentrations and bind to the channel in various ways, e.g. in open, inactivated or close states . Several of them also block the L‐calcium channel, counteracting the effect of the hERG channel block, and TCAs block Na + channels as well .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Antidepressants and antipsychotics classified with torsades de pointes arrhythmia risk and mortality in older adults ‐ a Swedish nationwide study

Danielsson¹,

Collin²,

Bergman³

et al. 2016

Brit J Clinical Pharma

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AIMThe aim of the study was to examine mortality risk associated with use of antidepressants and antipsychotics classified with torsades de pointes (TdP) risk in elderly. METHODSA matched case-control register study was conducted in people 65 years and older dying outside hospital from 2008-2013 (n = 286 092) and matched controls (n = 1 430 460). The association between prescription of antidepressants and antipsychotics with various TdP risk according to CredibleMeds (www.crediblemeds.org) and all-cause mortality was studied by multivariate conditional logistic regression adjusted for comorbidity and several other confounders. RESULTSUse of antidepressants classified with known or possible TdP risk, was associated with higher adjusted risk for mortality (OR 1.53, 95% CI 1.51, 1.56 and OR 1.63, 95% CI 1.61, 1.67, respectively) compared with antidepressants classified with conditional TdP risk (OR 1.25, 95% CI 1.22, 1.28) or without TdP classification (OR 0.99, 95% CI 0.94, 1.05). Antipsychotics classified with known TdP risk were associated with higher risk (OR 4.57, 95% CI 4.37, 4.78) than antipsychotics with possible risk (OR 2.58, 95% CI 2.52, 2.64) or without TdP classification (OR 2.14, 95% CI 2.03, 2.65). The following risk ranking was observed for commonly used antidepressants: mirtazapine > citalopram > sertraline > amitriptyline and for antipsychotics: haloperidol > risperidone >olanzapine > quetiapine. CONCLUSIONThe CredibleMeds system predicted drug-associated risk for mortality in the elderly at the risk class level. Among antipsychotics, haloperidol, and among antidepressants, mirtazapine and citalopram, were associated with the highest risks. The results suggest that the TdP risk with

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Section: Discussionmentioning

confidence: 99%

“…in open, inactivated or close states . Several of them also block the L‐calcium channel, counteracting the effect of the hERG channel block, and TCAs block Na + channels as well . The severe cardiac toxicity in overdose by TCAs seems to be related mainly to the block of Na + channels at high concentrations, rather than inhibition of IKr .…”

Section: Discussionmentioning

confidence: 99%

Antidepressants and antipsychotics classified with torsades de pointes arrhythmia risk and mortality in older adults ‐ a Swedish nationwide study

Danielsson¹,

Collin²,

Bergman³

et al. 2016

Brit J Clinical Pharma

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“…For situations when no in vitro data is available in silico predictions can be used. Presented in the tox-database.net collection can be directly used for QSAR models development [11,46]. …”

Section: Utility and Discussionmentioning

confidence: 99%

Tox-Database.net: a curated resource for data describing chemical triggered in vitro cardiac ion channels inhibition

Polak

Wiśniowska

Glinka

et al. 2012

BMC Pharmacol Toxicol

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BackgroundDrugs safety issues are now recognized as being factors generating the most reasons for drug withdrawals at various levels of development and at the post-approval stage. Among them cardiotoxicity remains the main reason, despite the substantial effort put into in vitro and in vivo testing, with the main focus put on hERG channel inhibition as the hypothesized surrogate of drug proarrhythmic potency. The large interest in the IKr current has resulted in the development of predictive tools and informative databases describing a drug's susceptibility to interactions with the hERG channel, although there are no similar, publicly available sets of data describing other ionic currents driven by the human cardiomyocyte ionic channels, which are recognized as an overlooked drug safety target.DiscussionThe aim of this database development and publication was to provide a scientifically useful, easily usable and clearly verifiable set of information describing not only IKr (hERG), but also other human cardiomyocyte specific ionic channels inhibition data (IKs, INa, ICa).SummaryThe broad range of data (chemical space and in vitro settings) and the easy to use user interface makes tox-database.net a useful tool for interested scientists.Database URLhttp://tox-database.net.

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“…If this data was not available, it was predicted with previously developed and described QSAR models (Polak et al, 2011(Polak et al, , 2012cWisniowska et al, 2012). It was assumed and confirmed in a subsequent QSAR based simulation that 3-OH quinidine also inhibits ionic currents.…”

Section: Ic50 -Concentration At Which the Ionic Current Is Inhibited mentioning

confidence: 96%

In vitro to human in vivo translation – pharmacokinetics and pharmacodynamics of quinidine

Polak

2013

ALTEX

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SummaryThe translational sciences aim to transfer results from basic research to the treatment of animals or patients. One of the approaches that could be utilized to achieve this goal is the in vitro-in vivo extrapolation (IVIVE) concepts of PK and PD mechanistic modeling and simulation to highlight the importance of assessing drug effect and safety in the preliminary phases of the drug development process. the IVIVe application approach necessitates the provision of three data sets: 1) drug related (ADMe processes and activity), 2) system data (describing population and variability of the chosen parameters), and 3) simulated trial design (Rostami-Hodjegan and tucker, 2007). the IVIVe methodology is a robust evaluation tool that assesses inter-individual variability based on the virtual population characteristics in the population study group.to assess the application value of the described approach, quinidine was selected as the model drug in the virtual study described here. the study endpoints covered plasma concentration of the parent compound and its main metabolite, 3-OH quinidine, from the pharmacokinetic side. either Qtc interval or the drug triggered change as compared to the baseline (ΔQT/ ΔQTc) were used as the pharmacodynamic effect descriptors. this pharmacodynamic effect dictates that drug cardiac safety should be regarded as a pivotal focal point of this study. Preclinical studies routinely use in vitro approaches to assess cardiac safety; however, non-rodent species (e.g., dogs, monkeys) are commonly used in the assessment procedure. this study proposes a novel concept based on a combination of mechanistic PBPK/PD modeling and simulation to predict the cardiac effects of drugs and thus help to incorporate the 3Rs concept

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Predictive model for L‐type channel inhibition: multichannel block in QT prolongation risk assessment

Cited by 15 publications

References 26 publications

Antidepressants and antipsychotics classified with torsades de pointes arrhythmia risk and mortality in older adults ‐ a Swedish nationwide study

Antidepressants and antipsychotics classified with torsades de pointes arrhythmia risk and mortality in older adults ‐ a Swedish nationwide study

Tox-Database.net: a curated resource for data describing chemical triggered in vitro cardiac ion channels inhibition

In vitro to human in vivo translation – pharmacokinetics and pharmacodynamics of quinidine

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