Drug Safety in preclinical studies

The development of new medicines is a long and expensive process. Despite growing efforts in R&D over the last decades, the attrition rate due to safety (especially cardiac toxicity) remains a major challenge for the pharmaceutical industry. Hence, safety assessment is of crucial importance during preclinical drug evaluation, and is particularly vital for upholding the integrity of the study and regulatory compliance.

Safety pharmacology studies are defined as those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions, in relation to exposure in the therapeutic range and above” (source ICH S7A).

Biotrial-preclinical-Drug-Safety

When you work with Biotrial, you are partnering with a global CRO with a team of preclinical experts holding extensive experience in drug safety and working in state-of-the-art laboratory facilities to deliver high quality data and reports.

Biotrial-preclinical-Eeg-Signals

Early Safety De-risking

Early safety de-risking is a process of conducting non-GLP safety studies early in the drug development process to reduce the risks, time delays, and costs of advancing basic research compounds. This approach can help to identify potential safety concerns early on so that they can be addressed before moving into more expensive and time-consuming GLP studies.

Biotrial offers a variety of early safety de-risking services and solutions, including:

  • Anesthetized and telemetered studies: anesthetized and fitted with telemetry devices to monitor their heart rate, blood pressure, and other physiological parameters, this study allows for the early detection of potential cardiac toxicity, as well as other safety concerns.
  • Rapid screening format for early detection of QT prolongation and other CV issues: This format uses a high-throughput approach to screen for potential QT prolongation and other cardiovascular safety concerns. This can help to identify potential problems early on, so that they can be addressed before moving into clinical trials.

By conducting early safety de-risking studies, Biotrial can help to improve the safety of new drugs and reduce the risk of costly failures in clinical trials.

 

The core battery of safety pharmacology studies is a set of tests that are conducted to investigate the potential effects of a drug on the central nervous, cardiovascular, and respiratory systems and anticipate future effects in patient trials. These systems are considered to be the most vital for life, and therefore, any potential adverse effects on these systems could have serious consequences. The core battery of safety pharmacology studies typically includes the following tests:

Central nervous system (CNS) studies

CNS studies are important in the safety assessment of new drugs because the brain and spinal cord are vital organ systems that control many important functions, such as movement, cognition, and behavior. CNS studies can help to identify potential adverse effects of drugs on the CNS, such as sedation, motor impairment, and cognitive dysfunction. These studies can also help to determine the safe dose range of a drug for the CNS.

By conducting CNS studies, Biotrial can help to ensure the safety of new drugs for the CNS. This is an important part of the drug development process, as it helps to protect patients from potential harm and protects the validity of a clients project.

  • Irwin Test / Functional Observational Battery
  • Rodents and large animals
  • Can be adapted according to your in-house protocol
Biotrial-preclinical-Follow-Up-Cardiovascular

Cardiovascular system (CVS) studies

CVS studies are important in the safety assessment of new drugs because the heart and blood vessels are vital organ systems that are essential for circulation and blood flow. CVS studies can help to identify potential adverse effects of drugs on the cardiovascular system, such as QT prolongation, arrhythmias, and heart failure. These studies can also help to determine the safe dose range of a drug for the cardiovascular system.

Biotrial offers a comprehensive range of CVS studies, including ECG, telemetry, and blood pressure measurements. These studies are conducted in rodents and large animals, such as dogs and monkeys.

  • Anesthetized and conscious models.
  • Rodents and large animals
  • Multi-frequency telemetry recording in group-housed animals
  • High quality ECG in chronically-instrumented animals
  • QT evaluation / Arrhythmias detection, according to ICH S7B

Respiratory system (RS)

Respiratory system (RS) studies are important in the safety assessment of new drugs because the lungs are a vital organ system that is essential for breathing and gas exchange. RS studies can help to identify potential adverse effects of drugs on the respiratory system, such as respiratory depression, bronchoconstriction, and pulmonary edema. These studies can also help to determine the safe dose range of a drug for the respiratory system.

  • Whole-body plethysmography in mouse, rat and guinea pig (IV route of administration possible)
  • Specific tests that are performed may vary depending on the drug and the species being studied.

Safety Pharmacology Studies: Follow-up and Supplemental Studies

Safety concerns may arise from core battery studies, clinical trials, other experimental in vitro or in vivo studies or from literature reports. If such potential adverse effects raise concern for human safety, these should be explored.

  • Supplemental Studies to evaluate potential adverse pharmacodynamic effects on organ systems not addressed by the core battery:
    • renal/urinary system (diuresis, electrolytes excretion, creatinine clearance, renal injury biomarkers)
    • Gastrointestinal System (GI motility, gastric emptying)
  • Follow-up studies to provide additional knowledge or greater depth of understanding on vital functions:
    • CNS (abuse liability, memory performance, seizure liability, change in sleep)
    • cardiovascular (cardiac output, ventricular contractility, vascular resistances, troponin)
    • Respiratory (pulmonary arterial pressure, airway resistance, blood gas analysis)
Biotrial preclinical Follow Up Cardiovascular 1
Biotrial preclinical Eeg Signal
Biotrial preclinical Follow Up Cns Brain
Biotrial preclinical Follow Up Respiratory

Resources

EEG Hypnos Poster
The Tilt test in non-human primate using manual restraint
Renal Biomarkers Poster
Guinea-Pig Telemetry Poster
Development of Quantitative Biomarkers of Drug-Induced Activation of the Reward System for Abuse Potential Assessment

ABSTRACT: Drug abuse liability is a growing concern for Regulatory Authorities and the
American opioid crisis raises the question of the evaluation of abuse potential
for new drugs.

  • Standard non-clinical methods are time/cost ineffective and rely on behavioral
    outcomes.
  • The need to develop more quantitative/predictive approaches has been
    pointed out.
  • Meanwhile, accumulating evidences highlight the role of initial activation of the reward system and its dysregulation in the development of drug addiction
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the tilt test in non-human primate using manual restraint: an improved method to investigate orthostatic hypotension

ABSTRACT: Drug-induced orthostatic hypotension (OH) is a common side-effect of medications such as antidepressants, antipsychotics, antiparkinsons, antihypertensives, vasodilators and diuretics. OH is defined as an excessive drop in arterial blood pressure resulting from a sudden postural change. Under physiological conditions, this phenomenon is compensated by the baroreflex, a regulatory mechanism that restores blood pressure by activating the sympathetic system leading to peripheral vasoconstriction and cardiac stimulation. However, this side-effect is not systematically addressed during preclinical drug development of NCE’s. The standard way to investigate OH in animals is the tilt test, as performed in humans. Physical restraint in modified chairs is the most frequently used technique in NHP. However, this restraint is stressful and can affect the results. We have developed a technique in cynomolgus monkeys using only manual restraint. Animals are regularly trained to the procedure using clicker training with positive reinforcement. Trained animals show no resistance during the procedure. The model was validated using two reference compounds, prazosin and hexamethonium.

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A cross species comparison study of undesired drug-induced hypothermia using telemetry
  • In a neuroscience drug discovery project, several compounds of interest induced
    severe albeit transient hypothermia after acute intraperitoneal or oral administration in
    a mouse pharmacology model
  • This hypothermia hindered exploration of efficacy in the in vivo mouse model and
    could possibly prevent the conduct of relevant safety studies in tox species at high
    dose levels
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The Conditioned Taste Aversion (CTA) Model in Rodents: A Potential Tool to Evaluate Drug-Induced Gastrointestinal Discomfort
  • Drug-related discomfort associated to effects like pain or intestinal disturbances may result in reduced treatment compliance and even drug discontinuation. For instance, GLP-1-based treatments are known to be associated with nausea and emesis in patients.
  • Conditioned taste aversion (CTA) is an associative learning process by which pairing the taste of a sweet liquid like a saccharin solution (conditioned stimulus) with
    gastrointestinal discomfort induced by another stimulus (unconditioned stimulus) leads to a conditioned aversive response upon re-exposure to the initial taste.
  • Since rodents are unable to display emesis, we aimed at evaluating the relevance of the CTA paradigm to detect gastrointestinal discomfort triggered by the GLP-1 pathway.
    We sought to evaluate the effects of an acute administration of semaglutide, a GLP-1 agonist, in the CTA test using a 2-bottle preference paradigm, in both mice and rats. Lithium
    chloride (LiCl) was used in the study as a positive reference compound.
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