Certara, the global biosimulation technology-enabled consultancy, announced the launch of version 2.0 of its Cardiac Safety Simulator (CSS), which has become a standalone product for the first time. CSS is currently being used by several leading pharma companies, two of which collaborated with Certara on its development. The subject area is also of great interest for regulatory scientists and agencies.

Drug-induced cardiovascular adverse events are one of the leading causes of drug withdrawals from the market and of drug label restrictions. As a result, biopharmaceutical companies are keen to identify new drug candidates with a propensity to cause arrhythmias, or the heart to beat with an abnormal rhythm, early in the R&D cycle.

ICH E14 guidance, which was introduced in 2005, required biopharmaceutical companies to conduct a ‘Thorough QT/QTc study (TQT)’ to assess the likelihood of a new drug candidate producing lethal ventricular arrhythmias. A TQT study requires a new drug candidate to be given to healthy volunteers in escalating doses, often up to the maximally-tolerated dose. The participant’s response to the drug is then monitored using high quality electrocardiograms (ECGs) to gain more understanding about its potential cardiotoxicity.

However, TQT studies are expensive and some scientists have expressed concern that they may result in the development of some drug candidates being stopped prematurely before the drug’s entire clinical profile has been evaluated.

“By enabling early cardiotoxicity risk to be measured more precisely, Certara’s Cardiac Safety Simulator is allowing biopharmaceutical companies to make more informed go/no-go decisions regarding their new drug candidates,” said Certara chief executive officer Edmundo Muniz, M.D., Ph.D. “It can cost $1-2 million to conduct a TQT study and they can take up to a year to complete depending on the group size and endpoints. We expect TQT studies to be replaced with properly-designed first-in-patient studies combined with in silico modeling in the next few years,” said Dr. Muniz.

“CSS can play a central role in the cardiotoxicity evaluation process by enabling early assessment of a drug’s pro-arrhythmic risk using in vitro data,” said Sebastian Polak, Ph.D., Certara’s Practice Lead for Cardiac Safety. “CSS integrates mechanistic physiologically-based pharmacokinetic (PK) modeling and simulation with a heart muscle cell model to predict a drug’s cardiac effects; it uses available in vitro data to simulate in vivo effects. CSS has the potential to replace TQT studies using ECG and PK data collected during Phase I ascending dose studies,” added Dr. Polak.

The US Food and Drug Administration (FDA) and the Cardiac Safety Research Consortium, of which Certara is a member, are currently evaluating alternatives to the TQT study, including biosimulation approaches such as those employed using CSS.

CSS can also be used in the early stages of drug development as a screening tool, even in situations where in-vitro data are not available.

CSS uses drug-triggered cardiac ion-current disruption data, together with predicted in-vivo exposure information to evaluate the factors influencing potential cardiac risk. It determines the drug candidate’s pro-arrhythmic potency by assessing its inhibition of several cardiac ion channels (multiple potassium, sodium and calcium). It also factors in population variability, examining the likely impact of demographic, physiological and genetic influences, including age, gender and ethnicity. In addition, it assesses the influence of multiple drugs on ventricular ion current and simulated ECGs to account for participants who may be receiving treatment for more than one condition.

CSS v2.0 offers many new features including: Provides enhanced QSAR models for predicting drug-triggered IKr, IKs, INa and ICaL current inhibition based on automatically-calculated phys-chem data (when in-vitro data are not available); Predicts population variability and drug-triggered physiology modifications;  Permits assessment of the potential impact of disease and genotypes; allows for genotype-related ionic current modification at the multiple channels level;  Contains an additional human left ventricular muscle cell model;  Evaluates up to seven chemical species (drugs, metabolites and other substances) simultaneously that are interacting at the ion channel(s) level;  Provides a new flexible, Excel-based tool to enhance visualization and analysis of simulation results.