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Chronic repeated-dose toxicity studies are required to support long-term dosing in late-stage clinical trials, providing data to adequately characterize adverse effects of potential concern for human safety. Different regulatory guidances for the design and duration of chronic toxicity studies are available, with flexibility in approaches often adopted for specific drug modalities. These guidances may provide opportunities to reduce time, cost, compound requirement and animal use within drug development programs if applied more broadly and considered outside their current scopes of use. This article summarizes presentations from a workshop at the 43rd Annual Meeting of the American College of Toxicology (ACT) in November 2022, discussing different approaches for chronic toxicity studies. A recent industry collaboration between the Netherlands Medicines Evaluation Board (MEB) and UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) illustrated current practices and the value of chronic toxicity studies for monoclonal antibodies (mAbs) and evaluated a weight of evidence (WOE) model where a 3-month study rather than a 6-month study might be adequate. Other topics included potential opportunities for single-species chronic toxicity studies for small molecules, peptides and oligonucleotides and whether a 6-month duration non-rodent study can be used more routinely than a 9-month study (similar to ICH S6(R1) for biological products). Also addressed were opportunities to optimize recovery animal use if warranted and whether restriction to one study only (if at all) can be applied more widely within and outside ICH S6(R1).
RESUMEN
To support registration of monoclonal antibodies (mAbs) for chronic indications, 6-month toxicity studies have historically been conducted. Experience with mAb development has shown a relatively benign and well-understood safety profile for this class, with most toxicity findings anticipated based on pharmacology. We evaluated whether a 6-month toxicity study is necessary to assess the long-term safety of mAbs. Data on First-in-Human (FIH)-enabling and chronic toxicity studies were shared for 142 mAbs submitted by 11 companies. Opportunities to further optimize study designs to reduce animal usage were identified. For 71% of mAbs, no toxicities or no new toxicities were noted in chronic studies compared to FIH-enabling study findings. New toxicities of potential concern for human safety or that changed trial design were identified in 13.5% of cases, with 7% being considered critical and 2% leading to program termination. An iterative, weight-of-evidence model which considers factors that influence the overall risk for a mAb to cause toxicity was developed. This model enables an evidence-based justification, suggesting when 3-month toxicity studies are likely sufficient to support late-stage clinical development and registration for some mAbs.
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Anticuerpos Monoclonales , Proyectos de Investigación , Animales , Humanos , Anticuerpos Monoclonales/toxicidadRESUMEN
Assessment of reversibility from nonclinical toxicity findings in animals with potential adverse clinical impact is required during pharmaceutical development, but there is flexibility around how and when this is performed and if recovery animals are necessary. For monoclonal antibodies (mAbs) and in accordance with ICH S6(R1) if inclusion of recovery animals is warranted, this need only occur in one study. Data on study designs for first-in-human (FIH)-enabling and later-development toxicity studies were shared from a recent collaboration between the NC3Rs, EPAA, Netherlands Medicines Evaluation Board (MEB) and 14 pharmaceutical companies. This enabled a review of practices on recovery animal use during mAb development and identification of opportunities to reduce research animal use. Recovery animals were included in 68% of FIH-enabling and 69% of later-development studies, often in multiple studies in the same program. Recovery groups were commonly in control plus one test article-dosed group or in all dose groups (45% of studies, each design). Based on the shared data review and conclusions, limiting inclusion of recovery to a single nonclinical toxicology study and species, study design optimisation and use of existing knowledge instead of additional recovery groups provide opportunities to further reduce animal use within mAb development programs.
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Anticuerpos Monoclonales , Proyectos de Investigación , Animales , Humanos , Anticuerpos Monoclonales/efectos adversos , Evaluación Preclínica de Medicamentos , Desarrollo de Medicamentos , Grupos ControlRESUMEN
ICH S6 (R1) states that safety evaluation of biotherapeutics should normally include 2 relevant species when available (i.e., a rodent and non-rodent species in which the test material is pharmacologically active), at least for short-term toxicology studies (generally supporting Phase I trials). For subsequent long-term toxicology studies (e.g., chronic studies up to 6 months dosing duration), there are options to reduce to only one species when justified, including when the mechanism of action of the biologic is well-understood or the toxicity findings in the short-term studies are "similar" in both the rodent and non-rodent species. Across the industry, around 25 to 33% of biologics assess multiple species within short-term toxicity studies but it is often unclear how different companies and regulators are applying the ICH S6 (R1) principles of "similar toxicity profiles" to progress with either 1 or 2 species in the long-term studies, in particular whether the absence of toxicities is considered within this definition. Sponsors may potentially continue to use 2 species to avoid regulatory risk and potential delays in development timelines, representing missed opportunities for reducing animal use, particularly of non-human primates, during drug development.This article summarizes presentations from a symposium at the 41st Annual meeting of the American College of Toxicology (ACT) in November 2020, in which industry case studies and regulatory perspectives addressed considerations and decisions for using 1 or 2 species for long-term toxicity studies, highlighting any common themes or experience that could be applicable for use in future decision-making.
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Desarrollo de Medicamentos , Animales , Humanos , Estados UnidosRESUMEN
In drug development, nonclinical safety assessment is pivotal for human risk assessment and support of clinical development. Selecting the relevant/appropriate animal species for toxicity testing increases the likelihood of detecting potential effects in humans, and although recent regulatory guidelines state the need to justify or dis-qualify animal species for toxicity testing, individual companies have developed decision-processes most appropriate for their molecules, experience and 3Rs policies. These generally revolve around similarity of metabolic profiles between toxicology species/humans and relevant pharmacological activity in at least one species for New Chemical Entities (NCEs), whilst for large molecules (biologics) the key aspect is similarity/presence of the intended human target epitope. To explore current industry practice, a questionnaire was developed to capture relevant information around process, documentation and tools/factors used for species selection. Collated results from 14 companies (Contract Research Organisations and pharmaceutical companies) are presented, along with some case-examples or over-riding principles from individual companies. As the process and justification of species selection is expected to be a topic for continued emphasis, this information could be adapted towards a harmonized approach or best practice for industry consideration.
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Evaluación Preclínica de Medicamentos/métodos , Industria Farmacéutica/métodos , Modelos Animales , Pruebas de Toxicidad/métodos , Productos Biológicos/toxicidad , Industria Farmacéutica/normas , Especificidad de la Especie , Pruebas de Toxicidad/normasRESUMEN
An international expert working group representing 37 organisations (pharmaceutical/biotechnology companies, contract research organisations, academic institutions and regulatory bodies) collaborated in a data sharing exercise to evaluate the utility of two species within regulatory general toxicology studies. Anonymised data on 172 drug candidates (92 small molecules, 46 monoclonal antibodies, 15 recombinant proteins, 13 synthetic peptides and 6 antibody-drug conjugates) were submitted by 18 organisations. The use of one or two species across molecule types, the frequency for reduction to a single species within the package of general toxicology studies, and a comparison of target organ toxicities identified in each species in both short and longer-term studies were determined. Reduction to a single species for longer-term toxicity studies, as used for the development of biologicals (ICHS6(R1) guideline) was only applied for 8/133 drug candidates, but might have been possible for more, regardless of drug modality, as similar target organ toxicity profiles were identified in the short-term studies. However, definition and harmonisation around the criteria for similarity of toxicity profiles is needed to enable wider consideration of these principles. Analysis of a more robust dataset would be required to provide clear, evidence-based recommendations for expansion of these principles to small molecules or other modalities where two species toxicity testing is currently recommended.
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Desarrollo de Medicamentos , Evaluación Preclínica de Medicamentos/efectos adversos , Pruebas de Toxicidad , Animales , Bases de Datos Factuales , Humanos , Medición de RiesgoRESUMEN
The acute toxicity 'six-pack' is a suite of tests for hazard identification and risk assessment, primarily conducted for the classification and labelling of industrial chemicals and agrochemicals. The 'six-pack' is designed to provide information on health hazards likely to arise from short-term exposure to chemicals via inhalation, oral and dermal routes, including the potential for eye and skin irritation/corrosion and skin sensitization. The component tests of the 'six-pack' currently rely heavily on the use of experimental animals. In 2017, the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), together with the European Union Reference Laboratory for Alternatives to Animal Testing (EURL-ECVAM), and the US National Toxicology Program (NTP) Centre for the Evaluation of Alternative Methods (NICEATM) held a workshop entitled 'Towards Global Elimination of the Acute Toxicity 'Six-Pack'' to explore opportunities to use alternative (non-animal) methods for hazard identification and classification without compromising human or environmental safety. The Workshop included scientists from regulatory agencies and industrial organisations worldwide, and sought to gain a more detailed understanding of the barriers to the adoption of suitable animal-free alternatives at an international level. Among the issues addressed were: the recurring theme of validation and scientific credibility, as well as the need for international standards, an understanding of the limitations of each new/alternative method and characterisation against the variability of current animal methods. The practicality and cost of new tests was also an important consideration. However, the need for mutual acceptance, and global harmonization of requirements were thought to be the major hurdle to overcome to realise a vision of the eventual complete elimination of the current, animal test-based, acute toxicity 'six-pack'.
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Alternativas a las Pruebas en Animales , Pruebas de Toxicidad Aguda/métodosRESUMEN
The pharmaceutical and biotechnology industries continually review the requirements for, and relevance of, safety assessment strategies. Various industry consortia are currently discussing and reviewing data on a range of topics with respect to regulatory toxicology programs. These consortia are charged with critical evaluation of data and the identification of opportunities to promote best practice and to introduce improved approaches to safety assessment. Such improvements may include enhanced predictivity, more efficient ways of working, and opportunities for promoting and implementing the 3Rs (replacement, refinement, or reduction). As each consortium is considering a distinct question, individual outputs and recommendations could be perceived to be conflicting. However, a common theme embraced by the consortia represented here is exploration of the most appropriate use of animals for the safety assessment of new medicinal products. This short review summarizes presentations and discussions from a symposium describing the work of four industry consortia and considers whether their recommendations can be aligned into realistic approaches to improve future toxicology testing strategies, highlighting justification for the appropriate use of different animal species and opportunities for reductions in animal use without compromising patient safety.
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Alternativas a las Pruebas en Animales , Desarrollo de Medicamentos , Animales , Anticuerpos Monoclonales/toxicidad , Bases de Datos Factuales , Humanos , Medición de Riesgo , Pruebas de ToxicidadRESUMEN
UNLABELLED: Limited toxicokinetic data is generated during modified Irwin screen and whole body plethysmography safety pharmacology studies, due to disturbance of primary endpoints by standard blood sampling methods. We evaluated if incorporation of microsampling would impact on data quality, as providing toxicokinetic data from main test animals could reduce the need for satellite animals. METHODS: A modified Irwin screen was performed, testing oral clonidine (0, 0.03, 0.1, or 0.3 mg/kg). One cohort of rats per dose level underwent standard blood sampling (post-4 h Irwin assessment), and another cohort underwent microsampling after the 0.5, 1, 2, 4 and 24 h Irwin assessments. The respiratory effects of oral theophylline (0 or 10 mg/kg) and oral baclofen (0 or 5 mg/kg), were tested using whole body plethysmography. Groups of animals underwent standard blood sampling (at end of recording at 4 h post-dose) or microsampling at either 0.5 h or 1 h intervals (4 or 8 microsamples, respectively). RESULTS: Microsampling did not impact on the quality of the data generated. The expected effects of clonidine on behavioural parameters, and of theophylline and baclofen on changes in ventilatory parameters were observed at a similar magnitude and duration independent of sampling method. DISCUSSION: The incorporation of multiple capillary microsamples into the modified Irwin or respiratory study did not adversely affect the primary endpoints. The capillary microsampling method is a refinement in blood sampling technique which can easily be adapted into safety pharmacology studies to generate pharmacokinetic profiles within the same animal as the primary data, thus enhancing scientific robustness and reducing the satellite animals required.
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Sistema Respiratorio/fisiopatología , Animales , Baclofeno/farmacología , Recolección de Muestras de Sangre/métodos , Masculino , Pletismografía Total/métodos , Ratas , Ratas Wistar , Sistema Respiratorio/efectos de los fármacos , Teofilina/farmacologíaRESUMEN
The aim of this investigation was to determine whether a shorter fasting period than the one historically employed for the charcoal meal test, could be used when measuring gastric emptying and intestinal transit within the same animal, and to ascertain whether the scientific outcome would be affected by this benefit to animal welfare. Rats and mice were fasted for 0, 3, 6 or 18 hours before the oral administration of vehicle or atropine. One hour later, the animals were orally administered a charcoal meal, then 20 minutes later, they were killed and the stomach and small intestine were removed. Intestinal transit time (the position of the charcoal front as a percentage of the total length of the small intestine) and relative gastric emptying (weight of stomach contents) were measured. Rats and mice fasted for six hours showed results for gastric emptying and intestinal transit which were similar to those obtained in animals fasted for 18 hours. Reducing the fasting period reduced the body weight loss in both species, and mice on shorter fasts could be group-housed, as hunger-induced fighting was lessened. Therefore, a fasting period of six hours was subsequently adopted for charcoal meal studies at our institution.
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Carbón Orgánico , Ayuno , Vaciamiento Gástrico , Tránsito Gastrointestinal , Animales , Peso Corporal , Masculino , Ratones , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
The National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) is working with industry to promote social housing during cardiovascular telemetry recordings within non-rodent safety pharmacology and toxicology studies. Following surveys to capture current practice, benefits and concerns to adoption of this refinement (2015 and 2017), a 2018 European workshop shared experience and practical advice to address common barriers such as sensitivity of different study designs and the potential for cross-contamination with test article in socially-housed conditions. A similar number of responses were received to each survey (38 in 2015; 36 in 2017), from biopharmaceutical companies and CROs that perform or outsource non-rodent telemetry studies. Each dataset had different respondents, but 19 facilities provided answers regarding dogs and non-human primates (NHPs) for both surveys. More respondents socially-housed their non-rodents in 2017; increases were apparent for both the non-recording/acclimatisation periods and the telemetry recording periods compared with 2015. However, on recording days only 60, 75 and 89% of respondents from Europe and 25, 14 and 36% of respondents from outside of Europe socially-housed their dogs, minipigs or NHPs respectively. The potential for contamination with test article between animals housed together is considered by some facilities as justification for individual housing during recordings, however, survey data did not support this rationale. Nine organisations provided data on prevalence of vomiting during telemetry studies, showing the risk was moderate for dogs and very low for minipig and NHP. Further, if vomiting did occur, this could be managed effectively with little impact on study outcomes or validity and with careful dose selection, the risk is further diminished. A recent increase in published papers and posters on this topic would suggest many more companies are planning, or have recently implemented, this refinement. The continued willingness of the community to share practical experience and publish validation data may lead to this approach becoming the 'new standard' across the industry in the near future, representing a core component of 'best-practice' recommendations to increase animal welfare whilst maintaining quality data provision for investigational and regulatory purposes.
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Electrocardiografía , Telemetría , Animales , Perros , Frecuencia Cardíaca , Vivienda para Animales , Porcinos , Porcinos EnanosRESUMEN
During the development of potential new medicines or agrochemicals, an assessment of the safety profile to humans and environmental species is conducted using a range of different in silico and in vitro techniques in conjunction with metabolism and toxicity studies using animals. The required studies are outlined within international regulatory guidelines which acknowledge and support the application of the 3Rs to reduce the number of animals used or to refine the procedures performed when these studies are deemed to be necessary. The continued development of new technologies and adoption of best-practice approaches to laboratory animal housing and study procedures has generated a series of refinements that can be incorporated into animal studies throughout the package. These refinements benefit the welfare of fish, mice, rats, rabbits, dogs, minipigs, and non-human primates (NHPs) whilst maintaining or improving data quality within general toxicology, metabolism, and other studies and can also bring efficiencies to processes that benefit study costs and timings. Examples are shared which cover the following topics: social housing of dogs and NHPs, surgical refinements in the rat bile duct cannulation model for collection of data for metabolism studies, whether fasting is really required prior to clinical pathology sampling, and the use of microsampling for toxicokinetics.
RESUMEN
Toxicity studies using mammalian species are generally required to provide safety data to support clinical development and licencing registration for potential new pharmaceuticals. International regulatory guidelines outline recommendations for the order (rodent and/or non-rodent) and number of species, retaining flexibility for development of a diverse range of drug modalities in a manner relevant for each specific new medicine. Selection of the appropriate toxicology species involves consideration of scientific, ethical and practical factors, with individual companies likely having different perspectives and preferences regarding weighting of various aspects dependent upon molecule characteristics and previous experience of specific targets or molecule classes. This article summarizes presentations from a symposium at the 2019 Annual Congress of the British Toxicology Society on the topic of species selection for pharmaceutical toxicity studies. This symposium included an overview of results from a National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) and Association of British Pharmaceutical Industry (ABPI) international collaboration that reviewed the use of one or two species in regulatory toxicology studies and justification for the species selected within each programme. Perspectives from two pharmaceutical companies described their processes for species selection for evaluation of biologics, and justification for selection of the minipig as a toxicological species for small molecules. This article summarizes discussions on the scientific justification and other considerations taken into account to ensure the most appropriate animal species are used for toxicity studies to meet regulatory requirements and to provide the most value for informing project decisions.
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Safety pharmacology is an essential part of drug development aiming to identify, evaluate and investigate undesirable pharmacodynamic properties of a drug primarily prior to clinical trials. In particular, cardiovascular adverse drug reactions (ADR) have halted many drug development programs. Safety pharmacology has successfully implemented a screening strategy to detect cardiovascular liabilities, but there is room for further refinement. In this setting, we present the INSPIRE project, a European Training Network in safety pharmacology for Early Stage Researchers (ESRs), funded by the European Commission's H2020-MSCA-ITN programme. INSPIRE has recruited 15 ESR fellows that will conduct an individual PhD-research project for a period of 36 months. INSPIRE aims to be complementary to ongoing research initiatives. With this as a goal, an inventory of collaborative research initiatives in safety pharmacology was created and the ESR projects have been designed to be complementary to this roadmap. Overall, INSPIRE aims to improve cardiovascular safety evaluation, either by investigating technological innovations or by adding mechanistic insight in emerging safety concerns, as observed in the field of cardio-oncology. Finally, in addition to its hands-on research pillar, INSPIRE will organize a number of summer schools and workshops that will be open to the wider community as well. In summary, INSPIRE aims to foster both research and training in safety pharmacology and hopes to inspire the future generation of safety scientists.
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Sistema Cardiovascular/efectos de los fármacos , Desarrollo de Medicamentos/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Farmacología/métodos , Humanos , SeguridadRESUMEN
Rat telemetry is widely used for biomedical research purposes and is used routinely in early pre-clinical drug development to screen for the potential cardiovascular risk of candidate drugs. Historically, these studies have been conducted in individually housed conditions which can impact significantly on an animal's welfare. Here we present data from a survey of pharmaceutical companies and contract research organisations to define current industry practices relating to the housing of rats during telemetry studies and to expand and complement a similar project in non-rodents. Results of the survey showed that 75% of respondents socially house rats on non-recording days of telemetry studies, whereas on recording days only 46% of respondents socially house the animals. When social housing is used on rat telemetry studies, rats are usually housed with an unrecorded companion animal. We also present and compare data from a telemetry study in standard individually ventilated cages (IVCs) with a study using new double-decker IVCs, both conducted using a companion animal approach. Telemetry signals were successfully collected from the double-decker IVCs without a loss of signal quality whilst offering a more spacious environment that allowed the animals to exhibit natural behaviours including full upright posture. Cardiovascular responses following pharmacological intervention with verapamil were similar when assessed in the standard and double-decker cages. Power analysis was conducted on pooled data from the studies in socially housed animals with preliminary results showing the power of detection of drug-induced effects is equivalent to previously published data in individually housed rats. This illustrates that telemetry recordings can be made from rats in socially housed conditions within standard or larger double-decker cages for the for the collection of cardiovascular telemetry data.
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Corazón/efectos de los fármacos , Vivienda para Animales , Telemetría/métodos , Bienestar del Animal , Animales , Presión Sanguínea/efectos de los fármacos , Sistema Cardiovascular/efectos de los fármacos , Electrocardiografía/efectos de los fármacos , Electrocardiografía/métodos , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Masculino , Ratas , Medio Social , Aislamiento Social , Verapamilo/farmacologíaRESUMEN
Regulatory guidelines recommend specialised safety pharmacology assessments in animals to characterise drug-induced effects on the central nervous system (CNS) prior to first-in-human trials, including the functional observational battery or Irwin test (here collectively termed neurofunctional assessments). These assessments effectively detect overtly neurotoxic drugs; however, the suitability of the in vivo assessments to readily detect more subtle drug effects on the nervous system has been questioned. A survey was formulated by an international expert working group convened by the (NC3Rs) to capture practice in CNS neurofunctional assessment tests and opinions on the perceived impact of in vivo test battery endpoints. Impact was defined as "the impact of measures alone/in combination on decision making in drug development or candidate selection when using the neurofunctional assessment". The results demonstrate that rodents are predominantly used for small molecule assessments, whereas non-rodents are frequently used to test biotherapeutics. Practice varied between respondents in terms of experimental design. Subsets of test battery endpoints were consistently considered highly impactful (e.g. convulsions, stereotypic behaviors); however, the perceived impact level of other endpoints varied depending whether drugs were designed for CNS targets. Many endpoints were considered to have no or minimal impact, whereas a subset of endpoints in CNS test batteries appears more impactful than others. A critical evaluation is required to assess whether the translational value of CNS in vivo safety pharmacology assessments could be increased by modifying or augmenting standard CNS test batteries. A revised approach to CNS safety assessment has the potential to reduce animal numbers without compromising patient safety.
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Desarrollo de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/métodos , Modelos Animales , Farmacología/métodos , Animales , Sistema Nervioso Central/efectos de los fármacos , Desarrollo de Medicamentos/legislación & jurisprudencia , Desarrollo de Medicamentos/estadística & datos numéricos , Evaluación Preclínica de Medicamentos/estadística & datos numéricos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Humanos , Farmacología/legislación & jurisprudencia , Proyectos de Investigación/legislación & jurisprudencia , Proyectos de Investigación/estadística & datos numéricos , Encuestas y CuestionariosRESUMEN
BACKGROUND: Evaluation of the effects of candidate drugs on the nervous system in preclinical safety pharmacology studies utilises a global neurobehavioral assessment, usually in the rat. This either takes the form of the functional observational battery (FOB) or modified Irwin Test, both of which evaluate effects across 4 functional domains: autonomic, neuromuscular, sensorimotor and behavioral. Although there is a great deal of overlap in the parameters they address, the two tests approach the assessments slightly differently. We undertook a broad pharmacological validation of both the FOB and the Irwin test, and compared the two outcomes. METHODS: Male rats (6 per treatment group) were used to assess each of 12 reference drugs alongside vehicle controls in separate FOB and Irwin studies. The drugs compared in the two study types were chlorpromazine, chlordiazepoxide, clonidine, baclofen, (+)-amphetamine, harmaline, 8-hydroxy-2-(di-n-propylamino)tetralin, buspirone, physostigmine, picrotoxin, yohimbine and atropine. There is a high degree of semantic equivalence in the parameters assessed in the autonomic domain between the two tests, with a lower degree of equivalence for neuromuscular and behavioral domains, whereas sensorimotor reflex testing in the FOB is far more extensive than in the Irwin test. RESULTS: Across the set of reference drugs, concordance between the two tests was generally good across the 4 functional domains at the 'domain' level (i.e., detecting 'an effect'), whereas there was generally a poor concordance at the individual parameter level. However, this was partially explained by variability between repeated studies on a single reference drug using the same test (FOB or Irwin). CONCLUSIONS: Both tests are 'fit-for-purpose' in detecting effects of candidate drugs on the nervous system. We would encourage the global safety pharmacology community to consider whether (a) the tests could be combined into one industry standard; (b) candidate drugs could be triaged according to CNS penetration, with the level of scrutiny in the CNS core battery assessment adjusted accordingly and (c) whether new home cage technology could be applied to semi-automate the preclinical neurobehavioral assessment.
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Sistema Nervioso Central/efectos de los fármacos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Preparaciones Farmacéuticas/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Evaluación Preclínica de Medicamentos/métodos , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
INTRODUCTION: The safety-related failure of drugs during clinical phases of development is a significant contributor to drug attrition, wasting resources and preventing treatments from reaching patients. A lack of concordance between results from animal models and adverse events in the clinic has been identified as one potential cause of attrition. In vitro models using human tissue or cells have the potential to replace some animal models and improve predictivity to humans. METHODS: To gauge the current use of human tissue models in safety pharmacology and the barriers to greater uptake, an electronic survey of the international safety assessment community was carried out and a Safety Pharmacology Society European Regional Meeting was organised entitled 'The Use of Human Tissue in Safety Assessment'. RESULTS: A greater range of human tissue models is in use in safety assessment now than four years ago, although data is still not routinely included in regulatory submissions. The barriers to increased uptake of the models have not changed over that time, with inadequate supply and characterisation of tissue being the most cited blocks. DISCUSSION: Supporting biobanking, the development of new human tissue modelling technology, and raising awareness in the scientific and regulatory communities are key ways in which the barriers to greater uptake of human tissue models can be overcome. The development of infrastructure and legislation in the UK to support the use of post-mortem or surgical discard tissue will allow scientists to locally source tissue for research.
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Bancos de Muestras Biológicas/tendencias , Evaluación Preclínica de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/tendencias , Animales , Bancos de Muestras Biológicas/normas , Evaluación Preclínica de Medicamentos/normas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Humanos , Modelos Animales , Obtención de Tejidos y Órganos/métodos , Obtención de Tejidos y Órganos/normas , Obtención de Tejidos y Órganos/tendenciasRESUMEN
INTRODUCTION: We evaluated the feasibility of providing food and water to rodents during whole body plethysmography (WBP) studies as a welfare improvement to standard conditions. METHODS: Male Han Wistar rats or CD1 mice (n=8) were placed in WBP chambers and respiratory parameters recorded for approximately 6h on four separate occasions. On each occasion the animals were exposed to a different plethysmography chamber environment using a randomised design: no food/water (the standard conditions), water bottle, hydrating gel and wet food. In a further session, rats (n=8) were administered theophylline, or vehicle and respiratory parameters measured in the plethysmography chamber containing wet food. RESULTS: Respiratory parameters of rats were not significantly altered by the provision of water or food. Providing wet food resulted in reduced body weight loss. Administration of theophylline caused the expected increase in respiratory rate. When mice were given access to hydrating gel or wet food the respiratory parameters were significantly affected; respiratory rate and tidal volume were increased. Providing wet food resulted in reduced bodyweight loss. DISCUSSION: The provision of food and water did not impact on respiratory parameters in rats placed in WBP chambers. When provided with wet food, rats lost less bodyweight. Therefore, to improve welfare conditions for rats during WBP respiratory studies wet food should be provided when appropriate to the study design. In mice, provision of food and water led to changes in respiratory parameters, therefore these improvements in welfare conditions are not suitable for mice.
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Bienestar del Animal , Exactitud de los Datos , Pletismografía Total/métodos , Frecuencia Respiratoria/fisiología , Volumen de Ventilación Pulmonar/fisiología , Animales , Estudios de Factibilidad , Alimentos , Masculino , Ratones , Modelos Animales , Ratas , Ratas Wistar , Frecuencia Respiratoria/efectos de los fármacos , Telemetría , Teofilina/farmacología , Volumen de Ventilación Pulmonar/efectos de los fármacos , Agua/fisiología , Pérdida de PesoRESUMEN
There has been significant focus on drug-induced QT interval prolongation caused by block of the human ether-a-go-go-related gene (hERG)-encoded potassium channel. Regulatory guidance has been implemented to assess QT interval prolongation risk: preclinical guidance requires a candidate drug's potency as a hERG channel blocker to be defined and also its effect on QT interval in a non-rodent species; clinical guidance requires a "Thorough QT Study" during development, although some QT prolonging compounds are identified earlier via a Phase I study. Clinical, heart rate-corrected QT interval (QTc) data on 24 compounds (13 positives; 11 negatives) were compared with their effect on dog QTc and the concentration of compound causing 50% inhibition (IC50) of hERG current. Concordance was assessed by calculating sensitivity and specificity across a range of decision thresholds, thus yielding receiver operating characteristic curves of sensitivity versus (1-specificity). The area under the curve of ROC curves (for which 0.5 and 1 indicate chance and perfect concordance, respectively) was used to summarize concordance. Three aspects of preclinical data were compared with the clinical outcome (receiver operating characteristic area under the curve values shown in brackets): absolute hERG IC50 (0.78); safety margin between hERG IC50 and clinical peak free plasma exposure (0.80); safety margin between QTc effects in dogs and clinical peak free plasma exposure (0.81). Positive and negative predictive values of absolute hERG IC50 indicated that from an early drug discovery perspective, low potency compounds can be progressed on the basis of a low risk of causing a QTc increase.