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

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.

[1]  M. Żurawska,et al.  Rapid pharmacological cardioversion of recent-onset atrial fibrillation using antazoline in elderly patients. , 2021, Polish archives of internal medicine.

[2]  S. Polak,et al.  Magnetic Core–Shell Molecularly Imprinted Nano-Conjugates for Extraction of Antazoline and Hydroxyantazoline from Human Plasma—Material Characterization, Theoretical Analysis and Pharmacokinetics , 2021, International journal of molecular sciences.

[3]  S. Polak,et al.  Characterization of In Vitro and In Vivo Metabolism of Antazoline Using Liquid Chromatography-Tandem Mass Spectrometry , 2020, International journal of molecular sciences.

[4]  P. Paśko,et al.  ANTAZOLINE RENAISSANCE IN THE TREATMENT OF CARDIAC ARRHYTHMIA: A REVIEW , 2020, Acta Poloniae Pharmaceutica - Drug Research.

[5]  M. Żurawska,et al.  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 , 2018, Cardiovascular therapeutics.

[6]  Malcolm Rowland,et al.  Physiologically Based Pharmacokinetic Model Qualification and Reporting Procedures for Regulatory Submissions: A Consortium Perspective , 2018, Clinical pharmacology and therapeutics.

[7]  A. Edginton.  Using Physiologically Based Pharmacokinetic Modeling for Mechanistic Insight: Cases of Reverse Translation , 2017, Clinical and translational science.

[8]  I. Kowalik,et al.  Efficacy and safety of antazoline in the rapid cardioversion of paroxysmal atrial fibrillation (the AnPAF Study) , 2017, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[9]  P. Kułakowski,et al.  Antazoline—insights into drug‐induced electrocardiographic and hemodynamic effects: Results of the ELEPHANT II substudy , 2017, Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc.

[10]  P. Milberg,et al.  Effective suppression of atrial fibrillation by the antihistaminic agent antazoline: First experimental insights into a novel antiarrhythmic agent , 2017, Cardiovascular therapeutics.

[11]  M. Żurawska,et al.  Comparative effectiveness and safety of antazoline‑based and propafenone‑based strategies for pharmacological cardioversion of short‑duration atrial fibrillation in the emergency department. , 2016, Polskie Archiwum Medycyny Wewnetrznej.

[12]  Joanna Giebułtowicz,et al.  Application of a novel liquid chromatography/tandem mass spectrometry method for the determination of antazoline in human plasma: Result of ELEPHANT-I [ELEctrophysiological, pharmacokinetic and hemodynamic effects of PHenazolinum (ANTazoline mesylate)] human pharmacokinetic study. , 2016, Journal of pharmaceutical and biomedical analysis.

[13]  I. Nakurte,et al.  The influence of pH on the stability of antazoline: kinetic analysis , 2015 .

[14]  Douglas E. V. Pires,et al.  pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures , 2015, Journal of medicinal chemistry.

[15]  A. Edginton,et al.  Physiologically Based Pharmacokinetic Modeling and Simulation in Pediatric Drug Development. , 2014, CPT: pharmacometrics & systems pharmacology.

[16]  S. Stec,et al.  Antazoline for rapid termination of atrial fibrillation during ablation of accessory pathways. , 2014, Cardiology journal.

[17]  I. Kowalik,et al.  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) , 2012, Trials.

[18]  A. Rostami-Hodjegan,et al.  Are there differences in the catalytic activity per unit enzyme of recombinantly expressed and human liver microsomal cytochrome P450 2C9? A systematic investigation into inter‐system extrapolation factors , 2011, Biopharmaceutics & drug disposition.

[19]  Malcolm Rowland,et al.  Mechanistic Approaches to Volume of Distribution Predictions: Understanding the Processes , 2007, Pharmaceutical Research.

[20]  S. Görög.  Ultraviolet-Visible Spectrophotometry in Pharmaceutical Analysis , 1995 .

[21]  Max D. Morris,et al.  Factorial sampling plans for preliminary computational experiments , 1991 .

[22]  M. Srzednicki,et al.  [Evaluation of the anti-arrhythmia effectiveness of Phenazolinum Polfa in paroxysmal atrial fibrillation]. , 1990, Polski tygodnik lekarski.

[23]  P. B. Marshall.  Some chemical and physical properties associated with histamine antagonism. , 1955, British journal of pharmacology and chemotherapy.