Title:

Development and performance verification of the pharmacokinetic model towards determination of the active drug fraction surrogate in the heart tissue

Author:

Tylutki, Zofia

Subject:

pharmacokinetics ; PBPK modeling ; drug safety

Abstract:

Accurate prediction of drug effect is invaluable in terms of both safety and efficacy. Cardioactive drugs may trigger their effects by binding to the targets from either the extra- or intracellular side of the sarcolemma. Knowledge of a drug concentration at its site of action is strongly needed to comprehend the exposure-response relationship and avoid the bias of the hysteresis effect in response vs. time profiles. The herein described doctoral project aimed to provide the tool, namely a physiologically-based cardiac pharmacokinetic model, which would be useful in assessment of the cardiac active drug fraction surrogate responsible for the clinically observed drug-related electrophysiological response in humans. Besides the model development, the concurrent goal of this research was to verify the model performance. The doctoral project resulted in establishment of the multicompartmental heart model structure nested in the full-PBPK model linked to the minimal-PBPK model for the metabolite. The final structure accounts for cardiac metabolism, passive diffusion and active transport as the ways of drug distribution within heart tissue, and distinguishes between extra- and intracellular spaces. It allows for the estimation of cardiac concentration of both parent compound and metabolites with inter-individual variability. Amitriptyline and its main metabolite, nortriptyline, were chosen as the exemplary drugs for model performance. The model was verified in terms of pharmacokinetics and the usefulness of predicted cardiac concentrations for modeling of amitriptyline-related electrophysiological effect.

Place of publishing:

Kraków

Level of degree:

2 - studia doktoranckie

Degree discipline:

farmakologia

Degree grantor:

Jagiellonian University. Medical College. Faculty of Pharmacy. Department of Social Pharmacy. Unit of Parmacoepidemiology and Pharmacoeconomics.

Promoter:

Sebastian Polak

Date:

2018

Date issued:

2018

Type:

Praca doktorska

Call number:

ZB-129271

ControlNumberVIRTUA:

click here to follow the link

Access rights:

nieograniczony

Location of original object:

Biblioteka Medyczna Uniwersytetu Jagiellońskiego- Collegium Medicum