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. 2022 Mar 20;15(3):379.
doi: 10.3390/ph15030379.

Development and Performance Verification of the PBPK Model for Antazoline and Its Metabolite and Its Utilization for Pharmacological Hypotheses Formulating

Barbara Wiśniowska  1 , Joanna Giebułtowicz  2 , Roman Piotrowski  3 , Piotr Kułakowski  3 , Sebastian Polak  1   4
Affiliations

Development and Performance Verification of the PBPK Model for Antazoline and Its Metabolite and Its Utilization for Pharmacological Hypotheses Formulating

Barbara Wiśniowska et al. Pharmaceuticals (Basel). .

Abstract

Antazoline is an antihistaminic drug that is effective in the termination of paroxysmal atrial fibrillation. Despite its long presence in the market, antazoline's ADME parameters and pharmacokinetic effects in humans are poorly characterized. The objective of this study was to fill this gap by generation of in vitro and in vivo data and the development of a physiologically based pharmacokinetic model describing antazoline and its main metabolite disposition. A set of ADME parameters for the antazoline and its hydroxy metabolite is provided based on literature data, QSAR predictions, in vitro binding and metabolic stability assays. These can be used to feed PBPK models. In our current work, the developed PBPK model simulating simultaneously the pharmacokinetic profile of antazoline and its metabolite was successfully verified against the available clinical data and the presented capability to account for the clinically observed variability. When used to feed the PD model (e.g., simulating ECG), concentration-time profiles predicted by the model enable the assessment of antazoline's effect in various clinical scenarios with the possibility to account for population differences or CP mediated drug-drug interactions.

Keywords: IVIVE; PBPK modelling; antazoline; atrial fibrillation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mean and individual simulated systemic plasma concentration profiles of antazoline and its metabolite following 100 mg of antazoline infusion (healthy volunteers, ELEPHANT I study). Dots—observed individual data; gray lines—5th and 95th percentile; green line—simulated average concentration; colour lines—simulated individual concentrations. Insert—data for the first 30 min after dosing.
Figure 2
Figure 2
Mean and individual simulated systemic plasma concentration profiles of antazoline and its metabolite following 300 mg antazoline infusion (healthy volunteers, ELEPHANT II study). Dots—observed individual data; gray lines—5th and 95th percentile; green line—simulated average concentration; colour lines—simulated individual concentrations.
Figure 3
Figure 3
Mean simulated systemic plasma concentrations profiles of antazoline and its metabolite following 100, 200, and 300 mg antazoline infusion (patients, ELEPHANT III study). Dots—observed individual data; gray lines—5th and 95th percentile; green line—simulated average concentration.
Figure 4
Figure 4
Results of sensitivity analysis for antazoline metabolite model parameters. µ*—the mean of absolute elementary effects of the tested parameter.
Figure 5
Figure 5
The main pathways of antazoline metabolism.
See this image and copyright information in PMC

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References

    1. Piotrowski R., Giebułtowicz J., Baran J., Sikorska A., Gralak-Łachowska D., Soszyńska M., Wroczyński P., Kułakowski P. Antazoline-Insights into Drug-Induced Electrocardiographic and Hemodynamic Effects: Results of the ELEPHANT II Substudy. Ann. Noninvasive Electrocardiol. 2017;22:e12441. doi: 10.1111/anec.12441. - DOI - PMC - PubMed
    1. Farkowski M.M., Maciag A., Dabrowski R., Pytkowski M., Kowalik I., Szwed H. Clinical Efficacy of Antazoline in Rapid Cardioversion of Paroxysmal Atrial Fibrillation—A Protocol of a Single Center, Randomized, Double-Blind, Placebo-Controlled Study (the AnPAF Study) Trials. 2012;13:162. doi: 10.1186/1745-6215-13-162. - DOI - PMC - PubMed
    1. Maciag A., Farkowski M., Chwyczko T., Beckowski M., Syska P., Kowalik I., Pytkowski M., Wozniak J., Dabrowski R., Szwed H. Efficacy and Safety of Antazoline in Rapid Cardioversion of Paroxysmal Atrial Fibrillation (the AnPAF Study) Europace. 2017;19:1637–1642. doi: 10.1093/europace/euw384. - DOI - PubMed
    1. Frommeyer G., Sterneberg M., Dechering D.G., Kaese S., Bögeholz N., Pott C., Fehr M., Bogossian H., Milberg P., Eckardt L. Effective Suppression of Atrial Fibrillation by the Antihistaminic Agent Antazoline: First Experimental Insights into a Novel Antiarrhythmic Agent. Cardiovasc. Ther. 2017;35:e12244. doi: 10.1111/1755-5922.12244. - DOI - PubMed
    1. Farkowski M.M., Maciag A., Zurawska M., Kowalik I., Szwed H., Pytkowski M. Clinical Effectiveness and Safety of Antazoline-Based Therapy in Patients with Stable Coronary Artery Disease Undergoing Pharmacological Cardioversion of Short-Duration Atrial Fibrillation in the Emergency Department. Cardiovasc. Ther. 2018;36:e12469. doi: 10.1111/1755-5922.12469. - DOI - PubMed

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