Abstract
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 ×10 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 “safe space” for post-approval risk management to identify high-risk clinical scenarios.
Highlights
Cardiac toxicity is one of the leading causes of high attrition rate at various stages of drug development, withdrawal of several marketed drugs, and re-labelling of manyElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.drugs [1,2,3,4]
The inhibition factor was calculated using MOXI concentrations simulated by the physiologically based pharmacokinetics (PBPK) model for the following bio-phases: (i) unbound
The results show that MOXI, an otherwise low torsade de pointes (TdP)-risk drug at therapeutic dose in a healthy subject with normal physiology, could cause TdP when combined with elevated patient physiological risk factors
Summary
Cardiac toxicity is one of the leading causes of high attrition rate at various stages of drug development, withdrawal of several marketed drugs, and re-labelling of many. Due to the potentially significant safety impact and corresponding regulatory concern of drug-induced cardiotoxicity, careful assessment of pro-arrhythmic potential is an integral part of pre-clinical and clinical safety evaluation of an investigational new drug (IND). There are several methods available for cardiac risk assessment, including in silico, in vitro, and ex vivo models as well as in vivo studies in animals and humans. Selection of the appropriate model is dependent upon the stage of development and the cardiac safety questions relevant to each development program. The most commonly utilized models during pre-clinical development include in vitro ion current inhibition models, where the human ion channels involved in cardiac electrophysiology are
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