New biosimulation solution addresses drug candidates’ cardiotoxicity risk
PRINCETON, NJ – Apr. 2, 2015 – Certara®, the global biosimulation technology-enabled consultancy, today 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.
薬物性の心血管系副作用は、医薬品の市場撤退の主な原因の1つであり、医薬品添付文書における使用制限に関連する事項の1つでもあります。そのため、心拍のリズムが異常を示す不整脈を引き起こす可能性の高い新薬候補を、研究開発の早期段階において同定することは、製薬企業にとって重要な関心事項です。
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.
しかし、QT/QTc評価試験は多額の費用を必要とするため、医薬品候補化合物の臨床プロファイルが全て明らかになる前に開発が早期に中止される可能性を懸念する科学者もいます。
“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.
米国食品医薬品局 (米国FDA) と当社も加盟する Cardiac Safety Research Consortium (心臓安全研究コンソーシアム) は、QT/QTc評価試験の代替手法としてCSSを用いたバイオシミュレーション手法などを現在評価しています。
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 the following:
- 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
Certara（サターラ）について
Certara is a global biosimulation technology-enabled consultancy. Its customers include hundreds of biopharmaceutical companies around the globe, together with several regulatory agencies. Certara’s solutions, which span the discovery, preclinical and clinical stages of drug development, enable data-driven decisions, leading to more precisely designed trials with a reduced risk of failure and improved subject safety. For more information, visit www.certara.com.
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