title: Virtual Clinical Trial Toward Polytherapy Safety Assessment: Combination of Physiologically Based Pharmacokinetic/Pharmacodynamic-Based Modeling and Simulation Approach With Drug-Drug Interactions Involving Terfenadine as an Example.
abstract: A Quantitative Systems Pharmacology approach was utilized to predict the cardiac consequences of drug-drug interaction (DDI) at the population level. The Simcyp in vitro-in vivo correlation and physiologically based pharmacokinetic platform was used to predict the pharmacokinetic profile of terfenadine following co-administration of the drug. Electrophysiological effects were simulated using the Cardiac Safety Simulator. The modulation of ion channel activity was dependent on the inhibitory potential of drugs on the main cardiac ion channels and a simulated free heart tissue concentration. ten Tusscher's human ventricular cardiomyocyte model was used to simulate the pseudo-ECG traces and further predict the pharmacodynamic consequences of DDI. Consistent with clinical observations, predicted plasma concentration profiles of terfenadine show considerable intra-subject variability with recorded Cmaxvalues below 5 ng/mL for most virtual subjects. The pharmacokinetic and pharmacodynamic effects of inhibitors were predicted with reasonable accuracy. In all cases, a combination of the physiologically based pharmacokinetic and physiology-based pharmacodynamic models was able to differentiate between the terfenadine alone and terfenadine + inhibitor scenario. The range of QT prolongation was comparable in the clinical and virtual studies. The results indicate that mechanistic in vitro-in vivo correlation can be applied to predict the clinical effects of DDI even without comprehensive knowledge on all mechanisms contributing to the interaction.
authors.affiliation: Unit of Pharmacoepidemiology and Pharmacoeconomics, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9 Street, Kraków 30-688, Poland. Electronic address: b.wisniowska@uj.edu.pl.
authors.forename: Barbara
authors.initials: B
authors.lastname: Wiśniowska
authors.affiliation: Unit of Pharmacoepidemiology and Pharmacoeconomics, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9 Street, Kraków 30-688, Poland; Simcyp (part of Certara), Blades Enterprise Centre, John Street, Sheffield S2 4SU, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Polak
mesh_terms: D000328:Adult; D002986:Clinical Trials as Topic / Q000379:methods*; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D039563:Histamine H1 Antagonists, Non-Sedating / Q000009:adverse effects / Q000378:metabolism*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D016593:Terfenadine / Q000009:adverse effects / Q000378:metabolism*; D014584:User-Computer Interface; D055815:Young Adult
chemical_list: D039563:Histamine H1 Antagonists, Non-Sedating; D016593:Terfenadine
keywords: QTc interval; clinical trial simulations; drug interactions; pharmacokinetic/pharmacodynamics models; proarrhythmia; terfenadine