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COVID-19 is a potentially fatal infection caused by the SARS-CoV-2 virus. The SARS-CoV-2 3CL protease (Mpro) is a viral enzyme essential for replication and is the target for nirmatrelvir. Paxlovid (nirmatrelvir co-administered with the pharmacokinetic enhancer ritonavir) showed efficacy in COVID-19 patients at high risk of progressing to hospitalization and/or death. Nonclinical safety studies with nirmatrelvir are essential in informing benefit-risk of Paxlovid and were conducted to support clinical development. In vivo safety pharmacology assessments included a nervous system/pulmonary study in rats and a cardiovascular study in telemetered monkeys. Potential toxicities were assessed in repeat dose studies of up to 1 month in rats and monkeys. Nirmatrelvir administration (1,000 mg/kg, p.o.) to male rats produced transient increases in locomotor activity and respiratory rate but did not affect behavioral endpoints in the functional observational battery. Cardiovascular effects in monkeys were limited to transient increases in blood pressure and decreases in heart rate, observed only at the highest dose tested (75 mg/kg per dose b.i.d; p.o.). Nirmatrelvir did not prolong QTc-interval or induce arrhythmias. There were no adverse findings in repeat dose toxicity studies up to 1 month in rats (up to 1,000 mg/kg daily, p.o.) or monkeys (up to 600 mg/kg daily, p.o.). Nonadverse, reversible clinical pathology findings without clinical or microscopic correlates included prolonged coagulation times at ≥60 mg/kg in rats and increases in transaminases at 600 mg/kg in monkeys. The safety pharmacology and nonclinical toxicity profiles of nirmatrelvir support clinical development and use of Paxlovid for treatment of COVID-19.
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Antivirais , Tratamento Farmacológico da COVID-19 , Animais , Antivirais/efeitos adversos , Masculino , RatosRESUMO
INTRODUCTION: The Safety Pharmacology Society (SPS) conducted a membership survey to examine industry practices related mainly to cardiovascular (CV) safety pharmacology (SP). METHODS: Questions addressed nonclinical study design, data analysis methods, drug-induced effects, and conventional and novel CV assays. RESULTS: The most frequent therapeutic area targeted by drugs developed by the companies/institutions that employ survey responders was oncology. The most frequently observed drug-mediated effects included an increased heart rate, increased arterial blood pressure, hERG (IKr) block, decreased arterial blood pressure, decreased heart rate, QTc prolongation, and changes in body temperature. Broadly implemented study practices included Latin square crossover study design with n = 4 for nonrodent CV studies, statistical analysis of data (eg, analysis of variance), use of arrhythmia detection software, and the inclusion of data from all study animals when integrating SP studies into toxicology studies. Most responders frequently used individual animal housing conditions. Responders commonly evaluated drug effects on multiple ion channels, but in silico modeling methods were used much less frequently. Most responders rarely measured the J-Tpeak interval in CV studies. Uncertainties relative to Standard for Exchange of Nonclinical Data applications for data derived from CV SP studies were common. Although available, the use of human induced pluripotent stem cell cardiomyocytes remains rare. The respiratory SP study was rarely involved with identifying drug-induced functional issues. Responders indicated that the study-derived no observed effect level was more frequently determined than the no observed adverse effect level in CV SP studies; however, a large proportion of survey responders used neither.
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Doenças Cardiovasculares/induzido quimicamente , Avaliação Pré-Clínica de Medicamentos/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Farmacologia/métodos , Animais , Sistema Cardiovascular , Interpretação Estatística de Dados , Indústria Farmacêutica , Humanos , Projetos de Pesquisa , Inquéritos e QuestionáriosRESUMO
INTRODUCTION: Based on the ICH S7B and E14 guidance documents, QT interval (QTc) is used as the primary in vivo biomarker to assess the risk of drug-induced torsades de pointes (TdP). Clinical and nonclinical data suggest that drugs that prolong the corrected QTc with balanced multiple ion channel inhibition (most importantly the l-type calcium, Cav1.2, and persistent or late inward sodium current, Nav1.5, in addition to human Ether-à-go-go-Related Gene [hERG] IKr or Kv11.1) may have limited proarrhythmic liability. The heart rate-corrected J to T-peak (JTpc) measurement in particular may be considered to discriminate selective hERG blockers from multi-ion channel blockers. METHODS: Telemetry data from Beagle dogs given dofetilide (0.3 mg/kg), sotalol (32 mg/kg), and verapamil (30 mg/kg) orally and Cynomolgus monkeys given medetomidine (0.4 mg/kg) orally were retrospectively analyzed for effects on QTca, JTpca, and T-peak to T-end covariate adjusted (Tpeca) interval using individual rate correction and super intervals (calculated from 0-6, 6-12, 12-18, and 18-24 hours postdose). RESULTS: Dofetilide and cisapride (IKr or Kv11.1 blockers) were associated with significant increases in QTca and JTpca, while sotalol was associated with significant increases in QTca, JTpca, and Tpeca. Verapamil (a Kv11.1 and Cav1.2 blocker) resulted in a reduction in QTca and JTpca, however, and increased Tpeca. Medetomidine was associated with a reduction in Tpeca and increase in JTpca. DISCUSSION: Results from this limited retrospective electrocardiogram analysis suggest that JTpca and Tpeca may discriminate selective IKr blockers and multichannel blockers and could be considered in the context of an integrated comprehensive proarrhythmic risk assessment.
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Bloqueadores dos Canais de Cálcio/farmacologia , Eletrocardiografia/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Animais , Biomarcadores , Cisaprida/farmacologia , Cães , Avaliação Pré-Clínica de Medicamentos , Síndrome do QT Longo/induzido quimicamente , Macaca fascicularis , Masculino , Medetomidina/farmacologia , Fenetilaminas/farmacologia , Sotalol/farmacologia , Sulfonamidas/farmacologia , Telemetria , Verapamil/farmacologiaRESUMO
Novel (non-fluoroquinolone) inhibitors of bacterial type II topoisomerases (NBTIs) are an emerging class of antibacterial agents. We report an optimized series of cyclobutylaryl-substituted NBTIs. Compound 14 demonstrated excellent activity both in vitro (S. aureus MIC90=0.125µg/mL) and in vivo (systemic and tissue infections). Enhanced inhibition of Topoisomerase IV correlated with improved activity in S. aureus strains with mutations conferring resistance to NBTIs. Compound 14 also displayed an improved hERG IC50 of 85.9µM and a favorable profile in the anesthetized guinea pig model.
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Antibacterianos/farmacologia , DNA Girase/metabolismo , DNA Topoisomerase IV/antagonistas & inibidores , Quinolinas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Inibidores da Topoisomerase/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , DNA Topoisomerase IV/metabolismo , Relação Dose-Resposta a Droga , Canais de Potássio Éter-A-Go-Go/metabolismo , Cobaias , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/enzimologia , Streptococcus pyogenes/efeitos dos fármacos , Streptococcus pyogenes/enzimologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/químicaRESUMO
Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis. In the 2-year carcinogenicity study with tofacitinib, increased incidence of hibernoma (a neoplasm of brown adipose tissue [BAT]) was noted in female rats at ≥30 mg/kg/day (≥41x human exposure multiples). Thus, signaling pathways within BAT were investigated by measuring BAT: weight, cell proliferation biomarkers, content of basal and prolactin-induced phosphorylated Signal Transducer and Activator of Transcription (STAT), and uncoupling protein 1 (UCP-1). The relationship between cardiovascular hemodynamics and plasma norepinephrine (NE) levels was also investigated. Tofacitinib administered to female rats at doses of 10, 30, or 75 mg/kg/day for 14 days increased BAT weight at 75 mg/kg/day and cell proliferation at ≥30 mg/kg/day. JAK inhibition, observed as lower pSTAT3 and pSTAT5 in BAT, was noted at ≥10 mg/kg/day, while lower activity of BAT was observed as lower UCP-1 protein at ≥30 mg/kg/day. In cultured brown adipocytes, prolactin-induced increase in pSTAT5 and pSTAT3 were inhibited by tofacitinib in a concentration-dependent manner. Tofacitinib lowered blood pressure, increased heart rate, and resulted in dose-dependent increases in circulating NE. Thus, JAK/STAT inhibition in BAT and sympathetic stimulation are two factors which might contribute to the genesis of hibernomas by tofacitinib in rats.
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Lipoma/induzido quimicamente , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/farmacologia , Lipoma/metabolismo , Masculino , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição STAT/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transativadores/efeitos adversos , Transativadores/farmacologiaRESUMO
Several classes of drugs have been shown to cause drug-induced vascular injury (DIVI) in preclinical toxicity studies. Measurement of blood flow and vessel diameter in numerous vessels and across various tissues by ultrasound imaging has the potential to be a noninvasive translatable biomarker of DIVI. Our objective was to demonstrate the utility of high-frequency ultrasound imaging for measuring changes in vascular function by evaluating blood flow and vessel diameter in the superior mesenteric arteries (SMA) of rats treated with compounds that are known to cause DIVI and are known vasodilators in rat: fenoldopam, CI-1044, and SK&F 95654. Blood flow, vessel diameter, and other parameters were measured in the SMA at 4, 8, and 24 hr after dosing. Mild to moderate perivascular accumulations of mononuclear cells, neutrophils in tunica adventitia, and superficial tunica media as well as multifocal hemorrhage and necrosis in the tunica media were found in animals 24 hr after treatment with fenoldopam and SK&F 95654. Each compound caused marked increases in blood flow and shear stress as early as 4 hr after dosing. These results suggest that ultrasound imaging may constitute a functional correlate for the microscopic finding of DIVI in the rat.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Ultrassonografia/métodos , Lesões do Sistema Vascular/induzido quimicamente , Lesões do Sistema Vascular/patologia , Animais , Azepinas/efeitos adversos , Fenoldopam/efeitos adversos , Hemodinâmica , Masculino , Artérias Mesentéricas/diagnóstico por imagem , Artérias Mesentéricas/efeitos dos fármacos , Niacinamida/efeitos adversos , Niacinamida/análogos & derivados , Piridazinas/efeitos adversos , Piridinas/efeitos adversos , Ratos , Ratos Sprague-Dawley , Lesões do Sistema Vascular/diagnóstico por imagemRESUMO
INTRODUCTION: Corrected QT interval (QTc)is an established biomarker for drug-induced Torsade de Pointe (TdP), but with concerns for a false positive signal. Clinically, JTpc and TpTec have emerged as ECG sub-intervals to differentiate predominant hERG vs. mixed ion channel blocking drugs that prolong QTc. METHODS: In a multicentric, prospective, controlled study, different proarrhythmic drug effects on QTc, JTpc and TpTec were characterized with cynomolgus monkeys using telemetry in a Lead II configuration for internal and external telemetry.Drugs and vehicle were administered orally (PO) to group size of 4 to 8 animals, in 4 laboratories. RESULTS: In monkeys, dofetilide (0.03-0.3 mg/kg) was associated with exposure dependent QTc and JTpc increase, but no significant TpTec effect. Similarly, quinidine (2-50 mg/kg) increased QTc and JTpc but did not change TpTec. Mexiletine (1-15 mg/kg) and verapamil (50 mg/kg) did not induce any significant effect on QTc, JTpc or TpTec. DISCUSSION: Clinically, predominant hERG blockers (dofetilide and quinidine) prolong QTc, JTpc and TpTec and are associated with increased risk for TdP. Results from this study demonstrate that ECG changes after dofetilide and quinidine administration to telemetered monkeys differ from the clinical response, lacking the expected effects on TpTec. Potential explanations for the lack of translation include physio-pharmacology species differences or ECG recording and analysis methodology variations. Mixed ion channel blockers verapamil and mexiletine administered to monkeys showed no significant QTc, JTpc or TpTec prolongation as expected based on the similar clinical response for these agents.
RESUMO
Compound-mediated locomotion changes, conducted via open field infrared photobeam breaks, are an important common component of neurological assessments conducted in safety pharmacology studies. In addition to open field locomotor activity assessments, activity data (derived from changes in signal strength) from cardiovascular (CV) telemetry studies can also be an alternative method potentially used to assess locomotor effects. However, comparisons of these two methods have not been extensively characterized. The goal of this work was to compare these two methodologies to assess activity in rats using reference compounds known to have central nervous system (CNS)-stimulant (preladenant) or CNS-depressant (chlorpromazine) effects. Open field activity was conducted using the Kinder Scientific Motor Monitor system and data were collected for 30 min at each drug's expected time of maximum plasma exposure (Tmax). Telemetry-based CV assessment data were continuously acquired using DSI radiotelemetry instrumented animals for 24 h postdose (HPD). Drugs were administered during the lights-on period for both study types. Administration of preladenant caused increases in activity within 0.5-2 HPD for both methods. While administration of chlorpromazine caused decreases in activity in the infrared beam-based open field assessment (1.0-1.5 HPD), there was no effect on telemetry-derived activity during a similar time period. However, telemetry-derived decreases in activity were observed during the lights-off period (16-20 HPD), suggesting CNS-depressant compounds may be mischaracterized if the optimal dose administration time is not selected based on the light/dark cycle and pharmacokinetics. Overall, these results suggest that telemetry-based activity assessment is capable of detecting CNS-stimulant effects of compounds.
Assuntos
Sistema Cardiovascular , Estimulantes do Sistema Nervoso Central , Ratos , Animais , Ratos Wistar , Clorpromazina , Estimulantes do Sistema Nervoso Central/farmacologia , Telemetria/métodosRESUMO
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).
Assuntos
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
INTRODUCTION: Characterization of the incidence of spontaneous arrhythmias to identify possible drug-related effects is often an important part of the analysis in safety pharmacology studies using telemetry. METHODS: A retrospective analysis in non-clinical species with and without telemetry transmitters was conducted. Electrocardiograms (24 h) from male and female beagle dogs (n = 131), Göttingen minipigs (n = 108) and cynomolgus non-human primates (NHP; n = 78) were analyzed. RESULTS: Ventricular tachycardia (VT) was observed in 3% of the dogs but was absent in minipigs and NHPs. Ventricular fibrillation (VF) was not observed in the 3 species. Ventricular premature beats (VPBs) were more frequent during daytime and atrioventricular blocks (AVBs) were more frequent at night in all species. A limited number of animals exhibited a high arrhythmia frequency and there was no correlation between animals with higher frequency of an arrhythmia type and the frequency of other arrythmias in the same animals. Clinical chemistry or hematology parameters were not different with or without telemetry devices. NHP with a transmural left ventricular pressure (LVP) catheter exhibited a greater incidence of VPBs and PJCs compared to telemetry animals without LVP. DISCUSSION: All species were similar with regards to the frequency of ventricular ectopic beats (26-46%) while the dog seemed to have more frequent junctional complexes and AVB compared to NHP and minipigs. Arrhythmia screening may be considered during pre-study evaluations, to exclude animals with abnormally high arrhythmia incidence.
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Arritmias Cardíacas , Telemetria , Animais , Cães , Suínos , Masculino , Feminino , Porco Miniatura , Incidência , Estudos Retrospectivos , EletrocardiografiaRESUMO
Norepinephrine reuptake inhibitors (NRIs) acutely increase norepinephrine (NE) levels, but therapeutic antidepressant activity is only observed after weeks of treatment because central NE levels progressively increase during continued drug exposure. Similarly, while NRIs acutely increase blood pressure (BP) and heart rate (HR) due to enhanced sympathetic neurotransmission, chronic treatment changes the responsiveness of the central noradrenergic system and suppresses these effects via autonomic regulation. To better understand the relationship between NE increases and cardiovascular safety, we investigated acute and chronic effects of the NRI reboxetine on central NE release and on BP and HR and electrical alternans, a measure of arrhythmia liability, in guinea pigs. NE release was assessed by microdialysis in medial prefrontal cortex (mPFC) and hypothalamic paraventricular nucleus (PVN); BP and HR were measured by telemetry. Animals were treated for 28 days with 15 mg/kg/day of reboxetine or vehicle via an osmotic minipump and then challenged with acute intravenous doses of reboxetine. Animals chronically treated with reboxetine had 2-fold higher extracellular basal NE levels in mPFC and PVN compared to basal levels after chronic vehicle treatment. BP was significantly increased after the first day of treatment, and gradually returned to vehicle levels by day 21. These data indicate that chronic NRI treatment may lead to an increase in central NE levels and a concomitant reduction in BP based on exposure-response curves compared to vehicle treatment, suggesting a larger separation between preclinical estimates of efficacy vs. safety compared to acute NRI treatment.
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Inibidores da Captação Adrenérgica/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Morfolinas/farmacologia , Norepinefrina/metabolismo , Inibidores da Captação Adrenérgica/administração & dosagem , Inibidores da Captação Adrenérgica/sangue , Animais , Córtex Cerebral/metabolismo , Dopamina/metabolismo , Esquema de Medicação , Cobaias , Bombas de Infusão Implantáveis , Morfolinas/administração & dosagem , Morfolinas/sangue , Norepinefrina/antagonistas & inibidores , Reboxetina , Serotonina/metabolismoRESUMO
INTRODUCTION: The use of high throughput patch clamp profiling to determine mixed ion channel-mediated arrhythmia risk was assessed using profiling data generated using proprietary internal and clinical reference compounds. We define the reproducibility of the platform and highlight inherent platform issues. The data generated was used to develop predictive models for cardiac arrhythmia risk, specifically Torsades de Pointes (TdP). METHODS: A retrospective analysis was performed using profiling data generated over a 3-year period, including patch clamp data from hERG, Cav1.2, and Nav1.5 (peak/late), together with hERG binding. RESULTS: Assay reproducibility was robust over the 3-year period examined. High throughput hERG patch IC50 values correlated well with GLP-hERG data (Pearson = 0.87). A disconnect between hERG binding and patch was observed for â¼10% compounds and trended with passive cellular permeability. hERG and Cav1.2 potency did not correlate for proprietary compounds, with more potent hERG compounds showing selectivity versus Cav1.2. For clinical compounds where hERG and Cav1.2 activity was more balanced, an analysis of TdP risk versus hERG/Cav1.2 ratio demonstrated low TdP probability when the hERG/Cav1.2 potency ratios were < 1. Modeling of clinical compound data revealed a lack of impact of the Nav1.5 (late) current in predicting TdP. Moreover, models using hERG binding data (ROC AUC = 0.876) showed an improved ability to predict TdP risk versus hERG patch clamp (ROC AUC = 0.787). DISCUSSION: The data highlight the value of high throughput patch clamp data in the prediction of TdP risk, as well as some potential limitations with this approach.
Assuntos
Canais de Potássio Éter-A-Go-Go , Torsades de Pointes , Humanos , Canais de Potássio Éter-A-Go-Go/metabolismo , Estudos Retrospectivos , Reprodutibilidade dos Testes , Torsades de Pointes/induzido quimicamente , Torsades de Pointes/metabolismo , Arritmias Cardíacas/induzido quimicamente , Canais Iônicos , Proteínas de Ligação a DNA/metabolismo , Canal de Potássio ERG1RESUMO
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.
Assuntos
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
Defining an appropriate and efficient assessment of drug-induced corrected QT interval (QTc) prolongation (a surrogate marker of torsades de pointes arrhythmia) remains a concern of drug developers and regulators worldwide. In use for over 15 years, the nonclinical International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and clinical ICH E14 guidances describe three core assays (S7B: in vitro hERG current & in vivo QTc studies; E14: thorough QT study) that are used to assess the potential of drugs to cause delayed ventricular repolarization. Incorporating these assays during nonclinical or human testing of novel compounds has led to a low prevalence of QTc-prolonging drugs in clinical trials and no new drugs having been removed from the marketplace due to unexpected QTc prolongation. Despite this success, nonclinical evaluations of delayed repolarization still minimally influence ICH E14-based strategies for assessing clinical QTc prolongation and defining proarrhythmic risk. In particular, the value of ICH S7B-based "double-negative" nonclinical findings (low risk for hERG block and in vivo QTc prolongation at relevant clinical exposures) is underappreciated. These nonclinical data have additional value in assessing the risk of clinical QTc prolongation when clinical evaluations are limited by heart rate changes, low drug exposures, or high-dose safety considerations. The time has come to meaningfully merge nonclinical and clinical data to enable a more comprehensive, but flexible, clinical risk assessment strategy for QTc monitoring discussed in updated ICH E14 Questions and Answers. Implementing a fully integrated nonclinical/clinical risk assessment for compounds with double-negative nonclinical findings in the context of a low prevalence of clinical QTc prolongation would relieve the burden of unnecessary clinical QTc studies and streamline drug development.
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Drogas em Investigação/efeitos adversos , Síndrome do QT Longo/induzido quimicamente , Animais , Arritmias Cardíacas/induzido quimicamente , Desenvolvimento de Medicamentos/métodos , Indústria Farmacêutica/métodos , Eletrocardiografia/métodos , Humanos , Medição de Risco , Torsades de Pointes/induzido quimicamenteRESUMO
This white paper presents principles for validating proarrhythmia risk prediction models for regulatory use as discussed at the In Silico Breakout Session of a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/US Food and Drug Administration-sponsored Think Tank Meeting on May 22, 2018. The meeting was convened to evaluate the progress in the development of a new cardiac safety paradigm, the Comprehensive in Vitro Proarrhythmia Assay (CiPA). The opinions regarding these principles reflect the collective views of those who participated in the discussion of this topic both at and after the breakout session. Although primarily discussed in the context of in silico models, these principles describe the interface between experimental input and model-based interpretation and are intended to be general enough to be applied to other types of nonclinical models for proarrhythmia assessment. This document was developed with the intention of providing a foundation for more consistency and harmonization in developing and validating different models for proarrhythmia risk prediction using the example of the CiPA paradigm.
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Arritmias Cardíacas/induzido quimicamente , Simulação por Computador , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Medição de Risco/métodos , Arritmias Cardíacas/prevenção & controle , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Humanos , Modelos Teóricos , Estudos de Validação como AssuntoRESUMO
Cardiovascular (CV) safety-related attrition is an important contributor to the loss of promising drug candidates during development. CV safety pharmacology studies are conducted to identify these safety effects. Understanding translation of CV endpoints (specifically, heart rate [HR], and blood pressure [BP]) across preclinical animal models and to the clinic is critical in developing a robust CV derisking strategy. To this end, we investigated translation of HR and BP endpoints using data from 83 compounds that were tested in telemetry studies in rat and large animal (LA; dog or monkey) and 79 compounds that were tested in LA telemetry studies and human phase I clinical trials. Sensitivity, specificity as well as predictive values were calculated for rat to LA model comparison and for LA to human studies comparison. The rat CV model showed good concordance (sensitivity = 84% and specificity = 71%) for LA BP and HR changes. Similarly, LA CV measures of HR and BP showed good concordance (sensitivity = 78% and specificity = 79%) to clinical changes. The CV effects generally occurred within 0.3-3× free plasma concentration across species. Directionality of BP and HR change was conserved between LA to humans. However, for rat to LA comparisons the directionality of change was opposite for 23%-26% compounds. In conclusion, these data establish the translation of HR and BP from preclinical to clinical studies and emphasize the importance of preclinical animal models in the examination of CV safety of drugs.
Assuntos
Doenças Cardiovasculares/induzido quimicamente , Desenvolvimento de Medicamentos/métodos , Hemodinâmica/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/fisiopatologia , Bases de Dados Factuais , Cães , Avaliação Pré-Clínica de Medicamentos , Haplorrinos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Segurança do Paciente , Ratos , Medição de Risco , Especificidade da Espécie , Pesquisa Translacional BiomédicaRESUMO
BACKGROUND AND PURPOSE: Translation of non-clinical markers of delayed ventricular repolarization to clinical prolongation of the QT interval corrected for heart rate (QTc) (a biomarker for torsades de pointes proarrhythmia) remains an issue in drug discovery and regulatory evaluations. We retrospectively analysed 150 drug applications in a US Food and Drug Administration database to determine the utility of established non-clinical in vitro IKr current human ether-à-go-go-related gene (hERG), action potential duration (APD) and in vivo (QTc) repolarization assays to detect and predict clinical QTc prolongation. EXPERIMENTAL APPROACH: The predictive performance of three non-clinical assays was compared with clinical thorough QT study outcomes based on free clinical plasma drug concentrations using sensitivity and specificity, receiver operating characteristic (ROC) curves, positive (PPVs) and negative predictive values (NPVs) and likelihood ratios (LRs). KEY RESULTS: Non-clinical assays demonstrated robust specificity (high true negative rate) but poor sensitivity (low true positive rate) for clinical QTc prolongation at low-intermediate (1×-30×) clinical exposure multiples. The QTc assay provided the most robust PPVs and NPVs (ability to predict clinical QTc prolongation). ROC curves (overall test accuracy) and LRs (ability to influence post-test probabilities) demonstrated overall marginal performance for hERG and QTc assays (best at 30× exposures), while the APD assay demonstrated minimal value. CONCLUSIONS AND IMPLICATIONS: The predictive value of hERG, APD and QTc assays varies, with drug concentrations strongly affecting translational performance. While useful in guiding preclinical candidates without clinical QT prolongation, hERG and QTc repolarization assays provide greater value compared with the APD assay.
Assuntos
Fármacos Cardiovasculares/farmacologia , Drogas em Investigação/farmacologia , Canais de Potássio Éter-A-Go-Go/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Fármacos Cardiovasculares/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/métodos , Drogas em Investigação/uso terapêutico , Canais de Potássio Éter-A-Go-Go/agonistas , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Frequência Cardíaca/fisiologia , Humanos , Síndrome do QT Longo/tratamento farmacológico , Síndrome do QT Longo/fisiopatologia , Estudos Retrospectivos , Torsades de Pointes/tratamento farmacológico , Torsades de Pointes/fisiopatologiaRESUMO
INTRODUCTION: Cardiac sodium channel antagonists have historically been used to treat cardiac arrhythmias by preventing the reentry of the electrical impulse that could occur following myocardial damage. However, clinical studies have highlighted a significant increase in mortality associated with such treatment. Cardiac sodium channel antagonist activity is now seen as an off-target pharmacology that should be mitigated during the drug development process. The aim of this study was to examine the correlation between in vitro/ex vivo assays that are routinely used to measure Nav1.5 activity and determine the translatability of the individual assays to QRS prolongation in the clinic. METHODS: A set of clinical compounds with known Nav1.5 activity was profiled in several in vitro/ex vivo assays (binding, membrane potential, patch clamp and the Langendorff isolated heart). Clinical data comprising compound exposure levels and changes in QRS interval were obtained from the literature. Sensitivity/specificity analysis was performed with respect to the clinical outcome. RESULTS: The in vitro assays showed utility in predicting QRS prolongation in the clinic. Optimal thresholds were defined for each assay (binding: IC20; membrane potential: IC10; patch clamp: IC20) and sensitivity (69-88%) and specificity (53-84%) values were shown to be similar between assay formats. DISCUSSION: The data provide clear statistical insight into the translatability of Nav1.5 antagonism data generated in vitro to potential clinical outcomes. These results improve our ability to understand the liability posed by such activity in novel development compounds at an early stage.