The effects of six antipsychotic agents on QTc—An attempt to mimic clinical trial through simulation including variability in the population

Glinka, Anna; Polak, Sebastian

doi:10.1016/j.compbiomed.2014.01.010

Cited by 21 publications

(12 citation statements)

References 25 publications

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“…Uncertainty in the unknown and estimated parameters has possibly contributed to the mismatch between clinical observations and the predicted values yet the general conclusions on the drugs triggered ECG modifications can be made. Such systematic deviation has not been observed in other simulations and studies including recently published work where the cardiac effect expressed as the QTc value of six central nervous system drugs was predicted using the Cardiac Safety Simulator 36 . Hence this mismatches could be attributed to lack of full knowledge of drug‐specific data and/or special conditions in the clinical study, which made them different to other more representative cases.…”

Section: Discussionmentioning

confidence: 81%

Interaction Between Domperidone and Ketoconazole: Toward Prediction of Consequent QTc Prolongation Using Purely In Vitro Information

Mishra

Polak

Jamei

et al. 2014

CPT Pharmacom & Syst Pharma

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We aimed to investigate the application of combined mechanistic pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation in predicting the domperidone (DOM) triggered pseudo-electrocardiogram modification in the presence of a CYP3A inhibitor, ketoconazole (KETO), using in vitro–in vivo extrapolation. In vitro metabolic and inhibitory data were incorporated into physiologically based pharmacokinetic (PBPK) models within Simcyp to simulate time course of plasma DOM and KETO concentrations when administered alone or in combination with KETO (DOM+KETO). Simulated DOM concentrations in plasma were used to predict changes in gender-specific QTcF (Fridericia correction) intervals within the Cardiac Safety Simulator platform taking into consideration DOM, KETO, and DOM+KETO triggered inhibition of multiple ionic currents in population. Combination of in vitro–in vivo extrapolation, PBPK, and systems pharmacology of electric currents in the heart was able to predict the direction and magnitude of PK and PD changes under coadministration of the two drugs although some disparities were detected.

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Section: Discussionmentioning

confidence: 81%

Interaction Between Domperidone and Ketoconazole: Toward Prediction of Consequent QTc Prolongation Using Purely In Vitro Information

Mishra

Polak

Jamei

et al. 2014

CPT Pharmacom & Syst Pharma

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“…Despite their usefulness, these strategies do not provide enough information about toxicity in the organism as an effect of the secondary metabolism derived from drugs, or the drug effects in other cellular lines present in the heart [76][77][78][79] . Primary cardiomyocytes derived from human embryonic stem cells [78] are used to evaluate cardiotoxicity; however the general consensus is that a reliable in vivo model is needed.…”

Section: Cardiotoxicity Of Small Molecules: Drug Screening Using the mentioning

confidence: 99%

“…In an attempt to evaluate toxicity of medicaments and other chemicals, new methodologies focusing on cardiomyocyte properties or computational models are under development [76,77] . Despite their usefulness, these strategies do not provide enough information about toxicity in the organism as an effect of the secondary metabolism derived from drugs, or the drug effects in other cellular lines present in the heart [76][77][78][79] .…”

Section: Cardiotoxicity Of Small Molecules: Drug Screening Using the mentioning

confidence: 99%

Zebrafish as Toxicological model for screening and recapitulate human diseases

Caballero¹,

Candiracci²

2018

JUMD

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Embryonic and larval Danio rerio (zebrafish) is increasingly used as a toxicological model to conduct rapid in vivo tests and developmental toxicity assays; the zebrafish features high genetic homology to mammals, robust, phenotypes, highthroughput genetic and chemical screening have made it a powerful tool to evaluate in vivo toxicity. New methodologies of genome editing as CRISPR/Cas9; ZFN and TALEN make it a suitable model to perform studies to pair human genetic diseases as well. This review surveys recent studies employing zebrafish as experimental model, comparing it with other in vivo and in vitro models, presenting zebrafish as a potent vertebrate tool to evaluate drug toxicity and efficacy in order to facilitate more extensive, easy and comprehensive knowledge of new generation drugs.

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“…The pharmacodynamic models built-in to CSS that can be used are O’Hara-Rudy64 and ten Tusscher6566 models. The simulation results, namely parameters characterizing depolarization (QRS) and repolarization (QT), will be compared against the available clinical data taking into account intra- and inter-individual human variability6768.…”

Section: Discussionmentioning

confidence: 99%

A four-compartment PBPK heart model accounting for cardiac metabolism - model development and application

Tylutki

Polak

2017

Sci Rep

Self Cite

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In the field of cardiac drug efficacy and safety assessment, information on drug concentration in heart tissue is desirable. Because measuring drug concentrations in human cardiac tissue is challenging in healthy volunteers, mathematical models are used to cope with such limitations. With a goal of predicting drug concentration in cardiac tissue, we have developed a whole-body PBPK model consisting of seventeen perfusion-limited compartments. The proposed PBPK heart model consisted of four compartments: the epicardium, midmyocardium, endocardium, and pericardial fluid, and accounted for cardiac metabolism using CYP450. The model was written in R. The plasma:tissues partition coefficients (Kp) were calculated in Simcyp Simulator. The model was fitted to the concentrations of amitriptyline in plasma and the heart. The estimated parameters were as follows: 0.80 for the absorption rate [h−1], 52.6 for Kprest, 0.01 for the blood flow through the pericardial fluid [L/h], and 0.78 for the P-parameter describing the diffusion between the pericardial fluid and epicardium [L/h]. The total cardiac clearance of amitriptyline was calculated as 0.316 L/h. Although the model needs further improvement, the results support its feasibility, and it is a first attempt to provide an active drug concentration in various locations within heart tissue using a PBPK approach.

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The effects of six antipsychotic agents on QTc—An attempt to mimic clinical trial through simulation including variability in the population

Cited by 21 publications

References 25 publications

Interaction Between Domperidone and Ketoconazole: Toward Prediction of Consequent QTc Prolongation Using Purely In Vitro Information

Interaction Between Domperidone and Ketoconazole: Toward Prediction of Consequent QTc Prolongation Using Purely In Vitro Information

Zebrafish as Toxicological model for screening and recapitulate human diseases

A four-compartment PBPK heart model accounting for cardiac metabolism - model development and application

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