Title:

The use of mathematical modeling approach in assessing the impact of variability in the population on drug pro-arrhythmic effect and clinical safety

Author:

Glinka, Anna

Subject:

pro-arrhythmic effect ; models ; QT ; variability

Abstract:

Pro-arrhythmic effect of drug application, including torsades de pointes (TdP) arrhythmia, became one of the major reasons for drugs to be withdrawn from the market. A great deal of in vitro methods that enable quick assessment of safety of new compounds in the early phases of their development was introduced to the research practice, which turned out to be effective as it resulted in the reduction of number of market withdrawals, however, limited precision of these methods poses a risk of a significant number of false positive signals. The analysis of drug triggered arrhythmia mechanisms shows how many factors determine the clinically observed effects. Mathematical modelling techniques enable to analyse this problem, beginning with the electrophysiological phenomena at the single cell level, up to ECG parameters. Part of the work was devoted to the analysis of the problem of inter-individual variability and its influence on cardiac effects of drugs. Firstly action potentials of single cells were simulated. Further analysis covered the QT interval length in the simulated ECG. The evaluation was conducted with the use of published results of clinical trials for selected drugs, which were compared with the results of computer simulations. In most cases, simulation process enabled to reconstruct trends in changes in the QT interval length observed in clinical trials.

Place of publishing:

Kraków

Level of degree:

2 - studia doktoranckie

Degree discipline:

choroby układu krążenia ; farmakologia

Degree grantor:

Uniwersytet Jagielloński. Collegium Medicum. Wydział Farmaceutyczny.

Promoter:

Sebastian Polak

Date:

2016

Date issued:

2015

Type:

Praca doktorska

Format:

application/pdf

Call number:

ZB-124669

ControlNumberVIRTUA:

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Language:

pol ; eng

Access rights:

tylko w bibliotece

Location of original object:

Biblioteka Medyczna Uniwersytetu Jagiellońskiego- Collegium Medicum