RESUMO
The voltage-gated sodium channel Nav1.7 is an attractive target for the treatment of pain based on the high level of target validation with genetic evidence linking Nav1.7 to pain in humans. Our effort to identify selective, CNS-penetrant Nav1.7 blockers with oral activity, improved selectivity, good drug-like properties, and safety led to the discovery of 2-substituted quinolines and quinolones as potent small molecule Nav1.7 blockers. The design of these molecules focused on maintaining potency at Nav1.7, improving selectivity over the hERG channel, and overcoming phospholipidosis observed with the initial leads. The structure-activity relationship (SAR) studies leading to the discovery of (R)-(3-fluoropyrrolidin-1-yl)(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinolin-2-yl)methanone (ABBV-318) are described herein. ABBV-318 displayed robust in vivo efficacy in both inflammatory and neuropathic rodent models of pain. ABBV-318 also inhibited Nav1.8, another sodium channel isoform that is an active target for the development of new pain treatments.
Assuntos
Dor , Canais de Sódio , Humanos , Dor/tratamento farmacológico , Manejo da Dor , Isoformas de Proteínas , Canais de Sódio/metabolismo , Relação Estrutura-AtividadeRESUMO
It is now well recognized that many lifesaving oncology drugs may adversely affect the heart and cardiovascular system, including causing irreversible cardiac injury that can result in reduced quality of life. These effects, which may manifest in the short term or long term, are mechanistically not well understood. Research is hampered by the reliance on whole-animal models of cardiotoxicity that may fail to reflect the fundamental biology or cardiotoxic responses of the human myocardium. The emergence of human induced pluripotent stem cell-derived cardiomyocytes as an in vitro research tool holds great promise for understanding drug-induced cardiotoxicity of oncological drugs that may manifest as contractile and electrophysiological dysfunction, as well as structural abnormalities, making it possible to deliver novel drugs free from cardiac liabilities and guide personalized therapy. This article briefly reviews the challenges of cardio-oncology, the strengths and limitations of using human induced pluripotent stem cell-derived cardiomyocytes to represent clinical findings in the nonclinical research space, and future directions for their further use.
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American Heart Association , Antineoplásicos/toxicidade , Cardiotoxicidade/genética , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Animais , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Células-Tronco Pluripotentes Induzidas/fisiologia , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , Estados Unidos/epidemiologiaRESUMO
Human stem cell-derived cardiomyocytes (hSC-CMs) hold great promise as in vitro models to study the electrophysiological effects of novel drug candidates on human ventricular repolarization. Two recent large validation studies have demonstrated the ability of hSC-CMs to detect drug-induced delayed repolarization and "cellrhythmias" (interrupted repolarization or irregular spontaneous beating of myocytes) linked to Torsade-de-Pointes proarrhythmic risk. These (and other) studies have also revealed variability of electrophysiological responses attributable to differences in experimental approaches and experimenter, protocols, technology platforms used, and pharmacologic sensitivity of different human-derived models. Thus, when evaluating drug-induced repolarization effects, there is a need to consider 1) the advantages and disadvantages of different approaches, 2) the need for robust functional characterization of hSC-CM preparations to define "fit for purpose" applications, and 3) adopting standardized best practices to guide future studies with evolving hSC-CM preparations. Examples provided and suggested best practices are instructional in defining consistent, reproducible, and interpretable "fit for purpose" hSC-CM-based applications. Implementation of best practices should enhance the clinical translation of hSC-CM-based cell and tissue preparations in drug safety evaluations and support their growing role in regulatory filings.
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Células-Tronco Adultas/efeitos dos fármacos , Arritmias Cardíacas/induzido quimicamente , Cardiotoxinas/toxicidade , Miócitos Cardíacos/efeitos dos fármacos , Guias de Prática Clínica como Assunto/normas , Estudos de Validação como Assunto , Células-Tronco Adultas/patologia , Células-Tronco Adultas/fisiologia , Arritmias Cardíacas/patologia , Arritmias Cardíacas/fisiopatologia , Humanos , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Miócitos Cardíacos/patologiaRESUMO
The Cardiac Safety Research Consortium (CSRC) is a transparent, public-private partnership that was established in 2005 as a Critical Path Program and formalized in 2006 under a Memorandum of Understanding between the United States Food and Drug Administration and Duke University. Our continuing goal is to advance paradigms for more efficient regulatory science related to the cardiovascular safety of new therapeutics, both in the United States and globally, particularly where such safety questions add burden to innovative research and development. This White Paper provides a summary of discussions by a cardiovascular committee cosponsored by the CSRC and the US Food and Drug Administration (FDA) that initially met in December 2014, and periodically convened at FDA's White Oak headquarters from March 2015 to September 2016. The committee focused on the lack of information concerning the cardiac effects of medications in the premature infant and neonate population compared with that of the older pediatric and adult populations. Key objectives of this paper are as follows: Provide an overview of human developmental cardiac electrophysiology, as well as the electrophysiology of premature infants and neonates; summarize all published juvenile animal models relevant to drug-induced cardiac toxicity; provide a consolidated source for all reported drug-induced cardiac toxicities by therapeutic area as a resource for neonatologists; present drugs that have a known cardiac effect in an adult population, but no reported toxicity in the premature infant and neonate populations; and summarize what is not currently known about drug-induced cardiac toxicity in premature infants and neonates, and what could be done to address this lack of knowledge. This paper presents the views of the authors and should not be construed to represent the views or policies of the FDA or Health Canada.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/complicações , Cardiopatias Congênitas/induzido quimicamente , Recém-Nascido Prematuro , Animais , Humanos , Lactente , Recém-NascidoRESUMO
The Cardiac Safety Research Consortium (CSRC), a transparent, public-private partnership established in 2005 as a Critical Path Program and formalized in 2006 under a Memorandum of Understanding between the United States Food and Drug Administration and Duke University, is entering its second decade. Our continuing goal is to advance paradigms for more efficient regulatory science related to the cardiovascular safety of new therapeutics, both in the United States and globally, particularly where such safety questions add burden to innovative research and development. Operationally, CSRC brings together a broad base of stakeholders from academia, industry, and government agencies in a collaborative forum focused on identifying barriers and then creating novel solutions through shared data, expertise, and collaborative research. This white paper provides a brief overview of the Consortium's activities in its first decade and a context for some of our current activities and future directions. The growth and success of the CSRC have been primarily driven by members' active participation and the development of goodwill and trust throughout our membership, which have facilitated novel collaborations across traditionally competitive or contentious stakeholder boundaries. The continued expansion of our base of participating academicians, industry experts, and regulators will define the Consortium's success in our second decade. It is our hope that sharing our endeavors to date will stimulate additional participation in the CSRC and also provide a model for other groups starting to develop similar collaborative forums.
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Pesquisa Biomédica , Fármacos Cardiovasculares , Procedimentos Cirúrgicos Cardiovasculares , Segurança de Equipamentos , Parcerias Público-Privadas , United States Food and Drug Administration , Universidades , Humanos , Segurança do Paciente , Estados UnidosRESUMO
Inhibition of the sphingosine-1-phosphate (S1P)-catabolizing enzyme S1P lyase (S1PL) elevates the native ligand of S1P receptors and provides an alternative mechanism for immune suppression to synthetic S1P receptor agonists. S1PL inhibition is reported to preferentially elevate S1P in lymphoid organs. Tissue selectivity could potentially differentiate S1PL inhibitors from S1P receptor agonists, the use of which also results in bradycardia, atrioventricular block, and hypertension. But it is unknown if S1PL inhibition would also modulate cardiac S1P levels or cardiovascular function. The S1PL inhibitor 6-[(2R)-4-(4-benzyl-7-chlorophthalazin-1-yl)-2-methylpiperazin-1-yl]pyridine-3-carbonitrile was used to determine the relationship in rats between drug concentration, S1P levels in select tissues, and circulating lymphocytes. Repeated oral doses of the S1PL inhibitor fully depleted circulating lymphocytes after 3 to 4 days of treatment in rats. Full lymphopenia corresponded to increased levels of S1P of 100- to 1000-fold in lymph nodes, 3-fold in blood (but with no change in plasma), and 9-fold in cardiac tissue. Repeated oral dosing of the S1PL inhibitor in telemeterized, conscious rats resulted in significant bradycardia within 48 hours of drug treatment, comparable in magnitude to the bradycardia induced by 3 mg/kg fingolimod. These results suggest that S1PL inhibition modulates cardiac function and does not provide immune suppression with an improved cardiovascular safety profile over fingolimod in rats.
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Aldeído Liases/antagonistas & inibidores , Bradicardia/induzido quimicamente , Inibidores Enzimáticos/efeitos adversos , Coração/efeitos dos fármacos , Lisofosfolipídeos/metabolismo , Miocárdio/metabolismo , Esfingosina/análogos & derivados , Animais , Bradicardia/metabolismo , Relação Dose-Resposta a Droga , Feminino , Coração/fisiologia , Masculino , Piperazinas/efeitos adversos , Ratos , Ratos Sprague-Dawley , Esfingosina/metabolismoRESUMO
In vitro screening for cardiovascular safety liabilities of novel drug candidates presents a challenge for the pharmaceutical industry. Such approaches rely on detecting pharmacologic effects on key components of complex integrated system early in drug discovery to define potential safety liabilities. Key to such studies are the concepts of hazard identification vs. risk assessment, drug specificity vs. selectivity, and an appreciation of the challenges faced when attempting to translate in vitro findings to preclinical in vivo as well as clinical effects. This chapter defines some key aspects of early safety pharmacology screening for cardiovascular liabilities, citing studies of two key depolarizing cardiac currents (fast sodium current and L-type calcium current) as examples linked to effects on cardiac conduction and repolarization.
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Avaliação Pré-Clínica de Medicamentos/métodos , Coração/efeitos dos fármacos , Canais de Cálcio Tipo L/efeitos dos fármacos , Cardiotoxicidade , Descoberta de Drogas , Indústria Farmacêutica , Humanos , Técnicas In Vitro , Medição de Risco , Segurança , Canais de Sódio/efeitos dos fármacosRESUMO
This white paper provides a summary of a scientific proposal presented at a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/Food and Drug Administration-sponsored Think Tank, held at Food and Drug Administration's White Oak facilities, Silver Spring, MD, on July 23, 2013, with the intention of moving toward consensus on defining a new paradigm in the field of cardiac safety in which proarrhythmic risk would be primarily assessed using nonclinical in vitro human models based on solid mechanistic considerations of torsades de pointes proarrhythmia. This new paradigm would shift the emphasis from the present approach that strongly relies on QTc prolongation (a surrogate marker of proarrhythmia) and could obviate the clinical Thorough QT study during later drug development. These discussions represent current thinking and suggestions for furthering our knowledge and understanding of the public health case for adopting a new, integrated nonclinical in vitro/in silico paradigm, the Comprehensive In Vitro Proarrhythmia Assay, for the assessment of a candidate drug's proarrhythmic liability, and for developing a public-private collaborative program to characterize the data content, quality, and approaches required to assess proarrhythmic risk in the absence of a Thorough QT study. This paper seeks to encourage multistakeholder input regarding this initiative and does not represent regulatory guidance.
Assuntos
Arritmias Cardíacas/induzido quimicamente , Avaliação Pré-Clínica de Medicamentos/métodos , Técnicas de Patch-Clamp/métodos , Arritmias Cardíacas/prevenção & controle , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Humanos , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/prevenção & controle , Medição de Risco , Torsades de Pointes/induzido quimicamente , Torsades de Pointes/prevenção & controle , Estados UnidosAssuntos
Antineoplásicos/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Desenvolvimento de Medicamentos , Coração/efeitos dos fármacos , Antineoplásicos Imunológicos/efeitos adversos , Biomarcadores/sangue , Cardiologistas , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Coleta de Dados , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imunoterapia/efeitos adversos , Oncologia , Projetos de Pesquisa , Trastuzumab/efeitos adversosRESUMO
This White Paper, prepared by members of the Cardiac Safety Research Consortium, discusses several important issues regarding the evaluation of blood pressure (BP) responses to drugs being developed for indications not of a direct cardiovascular (CV) nature. A wide range of drugs are associated with off-target BP increases, and both scientific attention and regulatory attention to this topic are increasing. The article provides a detailed summary of scientific discussions at a Cardiac Safety Research Consortium-sponsored Think Tank held on July 18, 2012, with the intention of moving toward consensus on how to most informatively collect and analyze BP data throughout clinical drug development to prospectively identify unacceptable CV risk and evaluate the benefit-risk relationship. The overall focus in on non-CV drugs, although many of the points also pertain to CV drugs. Brief consideration of how clinical assessment can be informed by nonclinical investigation is also outlined. These discussions present current thinking and suggestions for furthering our knowledge and understanding of off-target drug-induced BP increases and do not represent regulatory guidance.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Monitorização Ambulatorial da Pressão Arterial , Doenças Cardiovasculares/induzido quimicamente , Ensaios Clínicos como Assunto , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Humanos , Segurança do Paciente , Medição de RiscoRESUMO
Recent advances in electrocardiographic monitoring and waveform analysis have significantly improved the ability to detect drug-induced changes in cardiac repolarization manifested as changes in the QT/corrected QT interval. These advances have also improved the ability to detect drug-induced changes in cardiac conduction. This White Paper summarizes current opinion, reached by consensus among experts at the Cardiac Safety Research Consortium, on the assessment of electrocardiogram-based safety measurements of the PR and QRS intervals, representing atrioventricular and ventricular conduction, respectively, during drug development.
Assuntos
Doenças Cardiovasculares/fisiopatologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Antiarrítmicos/farmacologia , Ensaios Clínicos como Assunto , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Eletrocardiografia , Humanos , Medição de RiscoRESUMO
Cardiovascular (CV) safety concerns are a significant source of drug development attrition in the pharmaceutical industry today. Though current nonclinical testing paradigms have largely prevented catastrophic CV events in Phase I studies, many challenges relating to the inability of current nonclinical safety testing strategies to model patient outcomes persist. Contemporary approaches include a spectrum of evaluations of CV structure and function in a variety of laboratory animal species. These approaches might be improved with a more holistic integration of these evaluations in repeat-dose studies, addition of novel endpoints with greater sensitivity and translational application, and use of more relevant animal models. Particular opportunities present with advances in imaging capabilities applicable to rodent and non-rodent species, technical capabilities for measuring CV function in repeat-dose animal studies, detection and quantitation of microRNAs and wider use of alternative animal models. Strategic application of these novel opportunities considering putative CV risk associated with the molecular drug target as well as inherent risks present in the target patient population could tailor or 'personalize' nonclinical safety assessment as a more translational evaluation. This paper is a call to action for the clinical and nonclinical drug safety communities to assess these opportunities to determine their utility in filling potential gaps in our current cardiovascular safety testing paradigms.
Assuntos
Doenças Cardiovasculares/induzido quimicamente , Desenho de Fármacos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Animais , Modelos Animais de Doenças , Indústria Farmacêutica/métodos , Determinação de Ponto Final , Humanos , MicroRNAs/metabolismo , Projetos de Pesquisa , Medição de Risco/métodos , Especificidade da EspécieRESUMO
Recent updates and modifications to the clinical ICH E14 and nonclinical ICH S7B guidelines, which both relate to the evaluation of drug-induced delayed repolarization risk, provide an opportunity for nonclinical in vivo electrocardiographic (ECG) data to directly influence clinical strategies, interpretation, regulatory decision-making and product labeling. This opportunity can be leveraged with more robust nonclinical in vivo QTc datasets based upon consensus standardized protocols and experimental best practices that reduce variability and optimize QTc signal detection, i.e., demonstrate assay sensitivity. The immediate opportunity for such nonclinical studies is when adequate clinical exposures (e.g., supratherapeutic) cannot be safely achieved, or other factors limit the robustness of the clinical QTc evaluation, e.g., the ICH E14 Q5.1 and Q6.1 scenarios. This position paper discusses the regulatory historical evolution and processes leading to this opportunity and details the expectations of future nonclinical in vivo QTc studies of new drug candidates. The conduct of in vivo QTc assays that are consistently designed, executed and analyzed will lead to confident interpretation, and increase their value for clinical QTc risk assessment. Lastly, this paper provides the rationale and basis for our companion article which describes technical details on in vivo QTc best practices and recommendations to achieve the goals of the new ICH E14/S7B Q&As, see Rossman et al., 2023 (this journal).
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Síndrome do QT Longo , Humanos , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/diagnóstico , Drogas em Investigação/efeitos adversos , Eletrocardiografia , Medição de Risco , BioensaioRESUMO
The ICH E14/S7B Questions and Answers (Q&As) guideline introduces the concept of a "double negative" nonclinical scenario (negative hERG assay and negative in vivo QTc study) to demonstrate that a drug does not produce a clinically relevant QT prolongation (i.e., no QT liability). This nonclinical "double negative" data package, along with negative Phase 1 clinical QTc data, may be sufficient to substitute for a clinical Thorough QT (TQT) study in some specific cases. While standalone GLP in vivo cardiovascular studies in non-rodent species are standard practice during nonclinical drug development for small molecule programs, a variety of approaches to the design, conduct, analysis and interpretation are utilized across pharmaceutical companies and contract research organizations (CROs) that may, in some cases, negatively impact the stringent sensitivity needed to fulfill the new Q&As. Subject matter experts from both Pharma and CROs have collaborated to recommend best practices for more robust nonclinical cardiovascular telemetry studies in non-rodent species, with input from clinical and regulatory experts. The aim was to increase consistency and harmonization across the industry and to ensure delivery of high quality nonclinical QTc data to meet the proposed sensitivities defined within the revised ICH E14/S7B Q&As guideline (Q&As 5.1 and 6.1). The detailed best practice recommendations presented here cover the design and execution of the safety pharmacology cardiovascular study, including optimal methods for acquiring, analyzing, reporting, and interpreting the resulting QTc and pharmacokinetic data to allow for direct comparison to clinical exposures and assessment of safety margin for QTc prolongation.
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Sistema Cardiovascular , Síndrome do QT Longo , Humanos , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/diagnóstico , Telemetria , EletrocardiografiaRESUMO
Advances in non-clinical in vitro models, higher throughput approaches and the promise of human-derived preparations require methods to reliably assess the fidelity of translation of such assays, compared with in vivo models and clinical studies. This review discusses general principles and parameters useful to evaluate the value of non-clinical assays typically used to guide compound progression. I first consider the biological characteristics (including sensitivity and ability to replicate relevant responses) of models that form the foundation of an assay based on the questions posed. I then discuss the quantitative assessment of diagnostic performance and assay utility, including sensitivity and specificity, receiver operating characteristic curves, positive and negative predictive values, likelihood ratios, along with advantages of combining two independent assays. Understanding the strengths and limitations of the biological model employed along with assay performance and context of use is essential to selecting the best assays supporting the best drug candidates.
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Curva ROC , Humanos , Valor Preditivo dos Testes , Sensibilidade e EspecificidadeRESUMO
The content of this article derives from a Health and Environmental Sciences Institute (HESI) consortium with a focus to improve cardiac safety during drug development. A detailed literature review was conducted to evaluate the concordance between nonclinical repolarization assays and the clinical thorough QT (TQT) study. Food and Drug Administration and HESI developed a joint database of nonclinical and clinical data, and a retrospective analysis of 150 anonymized drug candidates was reviewed to compare the performance of 3 standard nonclinical assays with clinical TQT study findings as well as investigate mechanism(s) potentially responsible for apparent discrepancies identified. The nonclinical assays were functional (IKr) current block (Human ether-a-go-go related gene), action potential duration, and corrected QT interval in animals (in vivo corrected QT). Although these nonclinical assays demonstrated good specificity for predicting negative clinical QT prolongation, they had relatively poor sensitivity for predicting positive clinical QT prolongation. After review, 28 discordant TQT-positive drugs were identified. This article provides an overview of direct and indirect mechanisms responsible for QT prolongation and theoretical reasons for lack of concordance between clinical TQT studies and nonclinical assays. We examine 6 specific and discordant TQT-positive drugs as case examples. These were derived from the unique HESI/Food and Drug Administration database. We would like to emphasize some reasons for discordant data including, insufficient or inadequate nonclinical data, effects of the drug on other cardiac ion channels, and indirect and/or nonelectrophysiological effects of drugs, including altered heart rate. We also outline best practices that were developed based upon our evaluation.
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Síndrome do QT Longo , Torsades de Pointes , Potenciais de Ação , Animais , Eletrocardiografia , Coração , Humanos , Síndrome do QT Longo/induzido quimicamente , Estudos Retrospectivos , Torsades de Pointes/induzido quimicamenteRESUMO
INTRODUCTION: A successful integration of automated blood sampling (ABS) into the telemetry instrumented canine cardiovascular model is presented in this study. This combined model provides an efficient means to quickly gain understanding of potential effects on key cardiovascular parameters in dog while providing a complete Pharmacokinetic/Pharmacodynamic (PK/PD) profile for discovery compounds without handling artifacts, reducing the need for a separate pharmacokinetic study. METHODS: Male beagle dogs were chronically implanted with telemetry devices (PhysioTel™ model D70-PCTP) and vascular access ports (SPMID-GRIDAC-5NC). BASi Culex-L automated blood sampling (Bioanalytical Systems, Inc) system was used to collect blood samples at multiple time points. A series of four use cases utilizing four different test compounds and analytical endpoints are described to illustrate some of the potential applications of the technique. RESULTS: In the four presented use cases, automated blood sampling in telemetry instrumented dogs provides simultaneous cardiovascular (heart rate, arterial blood pressure, and left ventricular pressure), electrophysiological assessment (QTc, PR, and QRS intervals), body temperature, and animal activity, while collecting multiple blood samples for drug analysis. CONCLUSION: The combination of automated blood sampling with cardiovascular telemetry monitoring is a novel capability designed to support safety pharmacology cardiovascular assessment of discovery molecules. By combining telemetry and high-fidelity ABS, the model provides an enhanced PK/PD understanding of drug-induced hemodynamic and electrocardiographic effects of discovery compounds in conscious beagles in the same experimental session. Importantly, the model can reduce the need for a separate pharmacokinetic study (positive reduction 3R impact), reduces compound syntheses requirements, and shorten development timelines. Furthermore, implementation of this approach has also improved animal welfare by reducing the animal handling during a study, thereby reducing stress and associated data artifacts (positive refinement 3R impact).
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Sistema Cardiovascular , Telemetria , Animais , Pressão Sanguínea , Cães , Eletrocardiografia , Frequência Cardíaca , Macaca fascicularis , MasculinoRESUMO
INTRODUCTION: A successful integration of automated blood sampling (ABS) into the telemetry instrumented canine cardiovascular model is presented in this study. This combined model provides an efficient means to quickly gain understanding of potential effects on key cardiovascular parameters in dog while providing a complete Pharmacokinetic/Pharmacodynamic (PK/PD) profile for discovery compounds without handling artifacts, reducing the need for a separate pharmacokinetic study. METHODS: Male beagle dogs were chronically implanted with telemetry devices (PhysioTel™ model D70-PCTP) and vascular access ports (SPMID-GRIDAC-5NC). BASi Culex-L automated blood sampling (Bioanalytical Systems, Inc) system was used to collect blood samples at multiple time points. A series of four use cases utilizing four different test compounds and analytical endpoints are described to illustrate some of the potential applications of the technique. RESULTS: In the four presented use cases, automated blood sampling in telemetry instrumented dogs provides simultaneous cardiovascular (heart rate, arterial blood pressure, and left ventricular pressure), electrophysiological assessment (QTc, PR, and QRS intervals), body temperature, and animal activity, while collecting multiple blood samples for drug analysis. CONCLUSION: The combination of automated blood sampling with cardiovascular telemetry monitoring is a novel capability designed to support safety pharmacology cardiovascular assessment of discovery molecules. By combining telemetry and high-fidelity ABS, the model provides an enhanced PK/PD understanding of drug-induced hemodynamic and electrocardiographic effects of discovery compounds in conscious beagles in the same experimental session. Importantly, the model can reduce the need for a separate pharmacokinetic study (positive reduction 3R impact), reduces compound syntheses requirements, and shorten development timelines. Furthermore, implementation of this approach has also improved animal welfare by reducing the animal handling during a study, thereby reducing stress and associated data artifacts (positive refinement 3R impact).
Assuntos
Sistema Cardiovascular , Telemetria , Animais , Pressão Sanguínea , Cães , Eletrocardiografia , Frequência Cardíaca , MasculinoRESUMO
The integrative responses of the cardiovascular (CV) system are essential for maintaining blood flow to provide oxygenation, nutrients, and waste removal for the entire body. Progress has been made in independently developing simple in vitro models of two primary components of the CV system, namely the heart (using induced pluripotent stem-cell derived cardiomyocytes) and the vasculature (using endothelial cells and smooth muscle cells). These two in vitro biomimics are often described as immature and simplistic, and typically lack the structural complexity of native tissues. Despite these limitations, they have proven useful for specific "fit for purpose" applications, including early safety screening. More complex in vitro models offer the tantalizing prospect of greater refinement in risk assessments. To this end, efforts to physically link cardiac and vascular components to mimic a true CV microphysiological system (CVMPS) are ongoing, with the goal of providing a more holistic and integrated CV response model. The challenges of building and implementing CVMPS in future pharmacological safety studies are many, and include a) the need for more complex (and hence mature) cell types and tissues, b) the need for more realistic vasculature (within and across co-modeled tissues), and c) the need to meaningfully couple these two components to allow for integrated CV responses. Initial success will likely come with simple, bioengineered tissue models coupled with fluidics intended to mirror a vascular component. While the development of more complex integrated CVMPS models that are capable of differentiating safe compounds and providing mechanistic evaluations of CV liabilities may be feasible, adoption by pharma will ultimately hinge on model efficiency, experimental reproducibility, and added value above current strategies.