9 research outputs found
Real Patient and its Virtual Twin: Application of Quantitative Systems Toxicology Modelling in the Cardiac Safety Assessment of Citalopram
Abstract. A quantitative systems toxicology (QST) model for citalopram was established
to simulate, in silico, a âvirtual twinâ of a real patient to predict the occurrence of cardiotoxic
events previously reported in patients under various clinical conditions. The QST model
considers the effects of citalopram and its most notable electrophysiologically active primary
(desmethylcitalopram) and secondary (didesmethylcitalopram) metabolites, on cardiac
electrophysiology. The in vitro cardiac ion channel current inhibition data was coupled with
the biophysically detailed model of human cardiac electrophysiology to investigate the
impact of (i) the inhibition of multiple ion currents (IKr, IKs, ICaL); (ii) the inclusion of
metabolites in the QST model; and (iii) unbound or total plasma as the operating drug
concentration, in predicting clinically observed QT prolongation. The inclusion of multiple
ion channel current inhibition and metabolites in the simulation with unbound plasma
citalopram concentration provided the lowest prediction error. The predictive performance
of the model was verified with three additional therapeutic and supra-therapeutic drug
exposure clinical cases. The results indicate that considering only the hERG ion channel
inhibition of only the parent drug is potentially misleading, and the inclusion of active
metabolite data and the influence of other ion channel currents should be considered to
improve the prediction of potential cardiac toxicity. Mechanistic modelling can help bridge
the gaps existing in the quantitative translation from preclinical cardiac safety assessment to
clinical toxicology. Moreover, this study shows that the QST models, in combination with
appropriate drug and systems parameters, can pave the way towards personalised safety
assessment
Towards Bridging Translational Gap in Cardiotoxicity Prediction: an Application of Progressive Cardiac Risk Assessment Strategy in TdP Risk Assessment of Moxifloxacin
Drug-induced cardiac arrhythmia, especially occurrence of torsade de pointes (TdP), has been a leading cause of attrition and post-approval re-labeling and withdrawal of many drugs. TdP is a multifactorial event, reflecting more than just drug-induced cardiac ion channel inhibition and QT interval prolongation. This presents a translational gap in extrapolating pre-clinical and clinical cardiac safety assessment to estimate TdP risk reliably, especially when the drug of interest is used in combination with other QT-prolonging drugs for treatment of diseases such as tuberculosis. A multi-scale mechanistic modeling framework consisting of physiologically based pharmacokinetics (PBPK) simulations of clinically relevant drug exposures combined with Quantitative Systems Toxicology (QST) models of cardiac electro-physiology could bridge this gap. We illustrate this PBPK-QST approach in cardiac risk assessment as exemplified by moxifloxacin, an anti-tuberculosis drug with abundant clinical cardiac safety data. PBPK simulations of moxifloxacin concentrations (systemic circulation and estimated in heart tissue) were linked with in vitro measurements of cardiac ion channel inhibition to predict the magnitude of QT prolongation in healthy individuals. Predictions closely reproduced the clinically observed QT interval prolongation, but no arrhythmia was observed, even at Ă10 exposure. However, the same exposure levels in presence of physiological risk factors, e.g., hypokalemia and tachycardia, led to arrhythmic event in simulations, consistent with reported moxifloxacin-related TdP events. Application of a progressive PBPK-QST cardiac risk assessment paradigm starting in early development could guide drug development decisions and later define a clinical âsafe spaceâ for post-approval risk management to identify high-risk clinical scenarios