Development of an AOP for cardiotoxicity mediated by the blockade of L-type calcium channel
Lead Research Organisation:
Brunel University London
Department Name: Life Sciences
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
Calcium ions play a vital role in cellular and organism physiology. These ions are a central component of a complex system of intracellular messengers that mediates a wide range of biological processes. A diverse set of calcium channels contribute to the timely regulation of calcium currents at cellular level. Among them, the L-type calcium channel is responsible for the excitation-contraction coupling of skeletal, smooth, and cardiac muscle. Pharmaceuticals that unintentionally block this channel in cardiac cells may impair heart function and health, leading to various cardiac pathologies and predisposing individuals to heart failure. Advancing our understanding of the mechanisms underlying those adverse effects is of paramount importance if we want to develop effective strategies able to accurately predict potential cardiotoxicity as early as possible during drug development. The aim of this project is to develop an Adverse Outcome Pathway (AOP) that describes the series of causally related key events triggered by the blockade of L-type calcium channel, and that can ultimately lead to heart failure. This AOP will represent a valuable knowledge base able to guide the identification of key events that are highly predictive of in vivo toxicity, and that can be measured in vitro without relying on animal testing. The knowledge base will also be used as platform to drive future development projects aimed at incorporating additional layers of complexity in the model, and at driving the transition towards a fully quantitative AOP able to effectively support decision-making.
Planned Impact
The aim of this project is to develop an AOP that describes the cascade of causally related effects triggered by L-type calcium channel (LTCC) blockade, which can ultimately lead to heart failure.
This AOP may be useful in the following contexts:
-To predict cardiovascular safety liabilities for both new drug candidates and legacy pharmaceuticals that display unintended LTCC blocking activity.
-To improve our mechanistic understanding of the effects of different LTCC-blockers.
-To inform LTCC-blockers risk management and predict dose-dependent activation of specific regions of the AOP.
-To identify potential regions of cross-talk with other relevant pathways in specific clinical or disease contexts.
Specifically, the AOP will have impact on three major areas.
Impact on drug safety assessment
The prediction of cardiovascular safety liabilities is a major challenge in drug development, and a high number of in vivo studies are carried out to assess potential cardiotoxicity. The AOP developed in this project can play an important role to support pre-clinical safety assessment by giving the opportunity to frame the interpretation of in vitro and in silico data in a wider integrated multi-scale perspective. This AOP will also represent a valuable knowledge base that will drive future development projects aimed at incorporating quantitative factors in the model. A fully developed quantitative AOP for LTCC-blockade will be able to effectively guide the identification of key events that are highly predictive of in vivo toxicity, and that can be measured in vitro without relying on animal testing. Additionally, for those chemicals that are known to trigger not just LTCC, but multiple targets associated with potential cardiotoxicity (e.g. hERG), a network of relevant AOPs may represent a promising approach to support data interpretation, by guiding the identification of specific key events in the network that may lead to increased/decreased severity of apical adverse effects. This knowledge may be used, for example, to stop the development process because of safety concerns, or to guide tailored in vivo study design and endpoint selection, increasing the confidence in the resulting in vivo pre-clinical data.
Impact on LTCC-blockers risk management
LTCC-blockers are highly prescribed worldwide; the different drugs in the class can potentially display drug-specific toxicological profiles according to their affinity for the various LTCC sub-types differentially expressed in cell types or tissues. A fully developed AOP that incorporates information on the toxicological relevance of different sub-types of LTCCs may contribute to risk management by informing, for example, the identification of the most suitable LTCC-blocker for a given physiological/disease context.
Impact on drug environmental risk assessment
Since 2010, the European Union requires the submission of an environmental risk assessment (ERA) for all new drugs. The in vivo testing strategy used in the current ERA does not incorporate any mechanistic or predictive approach. This limitation makes the process heavily dependent on case-by-case in vivo assessment, and therefore unfit to embrace the 3Rs vision. AOPs, including the one developed in this project, have enormous potential to provide mechanistic rationale to the ERA, paving the way for the elimination of unnecessary in vivo testing (e.g. when the predicted blood concentrations in wild fish are much lower than those necessary to trigger target Ki), and the replacement of in vivo testing with in silico predictions (e.g. quantitative AOP). In the specific case of LTCC blockade, verapamil is the drug that has received more attention in terms of aquatic toxicity, but much less is known about the potential environmental impact of other LTCC-blockers. The AOP for LTCC-blockade and heart failure may provide full support to the ERA of those compounds with minimal use of in vivo testing.
This AOP may be useful in the following contexts:
-To predict cardiovascular safety liabilities for both new drug candidates and legacy pharmaceuticals that display unintended LTCC blocking activity.
-To improve our mechanistic understanding of the effects of different LTCC-blockers.
-To inform LTCC-blockers risk management and predict dose-dependent activation of specific regions of the AOP.
-To identify potential regions of cross-talk with other relevant pathways in specific clinical or disease contexts.
Specifically, the AOP will have impact on three major areas.
Impact on drug safety assessment
The prediction of cardiovascular safety liabilities is a major challenge in drug development, and a high number of in vivo studies are carried out to assess potential cardiotoxicity. The AOP developed in this project can play an important role to support pre-clinical safety assessment by giving the opportunity to frame the interpretation of in vitro and in silico data in a wider integrated multi-scale perspective. This AOP will also represent a valuable knowledge base that will drive future development projects aimed at incorporating quantitative factors in the model. A fully developed quantitative AOP for LTCC-blockade will be able to effectively guide the identification of key events that are highly predictive of in vivo toxicity, and that can be measured in vitro without relying on animal testing. Additionally, for those chemicals that are known to trigger not just LTCC, but multiple targets associated with potential cardiotoxicity (e.g. hERG), a network of relevant AOPs may represent a promising approach to support data interpretation, by guiding the identification of specific key events in the network that may lead to increased/decreased severity of apical adverse effects. This knowledge may be used, for example, to stop the development process because of safety concerns, or to guide tailored in vivo study design and endpoint selection, increasing the confidence in the resulting in vivo pre-clinical data.
Impact on LTCC-blockers risk management
LTCC-blockers are highly prescribed worldwide; the different drugs in the class can potentially display drug-specific toxicological profiles according to their affinity for the various LTCC sub-types differentially expressed in cell types or tissues. A fully developed AOP that incorporates information on the toxicological relevance of different sub-types of LTCCs may contribute to risk management by informing, for example, the identification of the most suitable LTCC-blocker for a given physiological/disease context.
Impact on drug environmental risk assessment
Since 2010, the European Union requires the submission of an environmental risk assessment (ERA) for all new drugs. The in vivo testing strategy used in the current ERA does not incorporate any mechanistic or predictive approach. This limitation makes the process heavily dependent on case-by-case in vivo assessment, and therefore unfit to embrace the 3Rs vision. AOPs, including the one developed in this project, have enormous potential to provide mechanistic rationale to the ERA, paving the way for the elimination of unnecessary in vivo testing (e.g. when the predicted blood concentrations in wild fish are much lower than those necessary to trigger target Ki), and the replacement of in vivo testing with in silico predictions (e.g. quantitative AOP). In the specific case of LTCC blockade, verapamil is the drug that has received more attention in terms of aquatic toxicity, but much less is known about the potential environmental impact of other LTCC-blockers. The AOP for LTCC-blockade and heart failure may provide full support to the ERA of those compounds with minimal use of in vivo testing.
