Safety pharmacological test/animal pharmacological test

2017-06-26

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Safety pharmacology is mainly to observe the adverse effects of the drug on the central nervous system, cardiovascular system and respiratory system when the drug is in the treatment range or above the treatment range. Additional and/or supplementary safety pharmacology studies that may be carried out as needed should also include observations of the urinary system, autonomic nervous system, digestive system and other organs and tissues. The purpose and significance of safety pharmacology research is to discover undesirable pharmacological effects that may be related to clinical safety, evaluate adverse reactions or pathological effects observed in toxicological tests or clinical studies, and explore the mechanism of adverse reactions.

Test type	Animal species	Type of drug	Route of administration	Research content
Safe pharmacology	Mouse Rat Guinea pig Rabbit Beagles	Small molecule biological Natural products vaccine traditional Chinese medicine	Oral: gavage, capsule Parenteral: intraperitoneal injection, intravenous injection, intramuscular injection, intradermal injection, subcutaneous injection, continuous infusion, intravitreal injection Other: nasal feeding, nasal cavity, eyes, rectum, vagina, implant	Cardiovascular system (anaesthetized animals/awake animals) Central nervous system: spontaneous activity test in mice, runner test in mice, prolonged sleep time test of pentobarbital sodium in mice, subthreshold hypnotic dose test in mice Cardiovascular system: blood pressure, electrocardiogram, heart rate, etc. before and after administration Respiratory system: respiration rate and depth of respiration before and after administration Supplementary test

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The safety pharmacology studies are designed to reveal any functional effects on the cardiovascular, respiratory, central nervous, gastrointestinal, renal, autonomic nervous and other organ systems. It is generally required that the core battery of safety pharmacology studies (assessment of effects on cardiovascular, central nervous and respiratory systems) be completed before the Phase I clinical trial.

What are safety pharmacology core battery studies?

The purpose of the safety pharmacology core battery is to investigate the effects of the test substance on vital functions. In this regard, the cardiovascular, respiratory and central nervous systems are usually considered the vital organ systems that should be studied in the core battery.

Central Nervous System

Effects of the test substance on the central nervous system should be assessed appropriately. Motor activity, behavioral changes, coordination, sensory/motor reflex responses and body temperature should be evaluated.

Cardiovascular System

Effects of the test substance on the cardiovascular system should be assessed appropriately. Blood pressure, heart rate, and the electrocardiogram should be evaluated. In vivo, in vitro and/or ex vivo evaluations, including methods for repolarization and conductance abnormalities, should also be considered.

Respiratory System

Effects of the test substance on the respiratory system should be assessed appropriately. Respiratory rate and other measures of respiratory function (e.g., tidal volume or hemoglobin oxygen saturation) should be evaluated. Clinical observation of animals is generally not adequate to assess respiratory function, and thus these parameters should be quantified by using appropriate methodologies.

Adverse effects may be suspected based on the pharmacological properties or chemical class of the test substance. Additionally, concerns may arise from the safety pharmacology core battery, clinical trials, pharmacovigilance, experimental in vitro or in vivo studies, or from literature reports. When such potential adverse effects raise concern for human safety, these should be explored in follow-up or supplemental safety pharmacology studies, as appropriate.

What are Follow-up safety pharmacology research Follow-up studies are meant to provide a greater depth of understanding than, or additional knowledge to, that provided by the core battery on vital functions.

Central Nervous System

The central nervous system controls the body's use, thinking, emotion, consciousness, immune system, and neuroendocrine system, and is an important system for maintaining life.

Therefore, in drug development, it is necessary to pay attention to the side effects of the central nervous system and observe the effects of drugs on behavioral activities (e.g. behavioral despair experiment, forced swimming experiment, anticonvulsant experiment, anti-aggressive behavior experiment, light-dark through-box experiment, elevated cross maze experiment), learning memory (jumping table experiment, dark avoidance experiment, light-dark through-box experiment, etc.).

Neurobiochemical (e.g., determination of neurotransmitters and their corresponding receptors in the brain), visual, auditory, and/or electrophysiological effects.

Cardiovascular system

Cardiovascular adverse reactions from drugs are an important cause of drug withdrawal and discontinuation of development, therefore, during drug development, attention needs to be paid not only to the risk that drugs may induce arrhythmias leading to sudden death, but also to the effects of drugs on myocardial contractile function and peripheral vasculature.

For example, observe the effects of drugs on cardiovascular functions such as cardiac output, myocardial contractility and vascular resistance, and explore their mechanisms of action.

Respiratory system

Observe the effects of drugs on airway resistance, pulmonary respiratory flow, pulmonary artery pressure, blood gas analysis, etc.

Supplementary safety pharmacology research shall be conducted as required

What are Supplemental Safety Pharmacology Studies

Supplemental Safety Pharmacology tests are studies that are not covered in core combination tests or repeated administration toxicity tests, but are required for drug safety considerations.

Urinary/renal system

If the data suggest that the drug novelty or its known metabolites are primarily eliminated by the kidneys, then a safety pharmacology study of the urinary/renal system is necessary prior to first application to humans. Observe the effect of the drug on renal function, such as measuring urine volume, specific gravity, osmolality, pH, electrolyte balance, urine protein urine glucose, cellular and blood biochemistry (e.g., urea ammonia, creatinine, protein).

Such studies are usually performed in rats and can also be combined with toxicity tests (rat, canine, non-human primate toxicity tests).

Autonomic system

The effects of the drug on the autonomic system, such as binding to receptors related to the autonomic system, functional responses to agonists or antagonists in vivo or in vitro, direct stimulatory effects on the autonomic nerves and effects on cardiovascular responses, stress reflexes and heart rate.

Digestive system

For drugs by the oral route of administration, safety pharmacology studies of the gastrointestinal system are required before the first application to humans to observe the effects of the drug on the gastrointestinal digestive system.

This includes the determination of gastric juice secretion and pH, gastrointestinal injury, bile secretion, in vivo drug transit time, and in vitro ileal contraction test.

Drugs by other routes of administration are generally not required for safety pharmacology studies of the gastrointestinal system unless gastrointestinal toxicity is present.

The effects of potential drug dependence, skeletal muscle, immune and endocrine function, etc., also need to be evaluated accordingly.

Conditions under Which Safety Pharmacology Studies Are Not Necessary

Safety pharmacology studies may not be required for topically applied agents (e.g., dermal or ocular) where the pharmacological profile of the test substance has been adequately characterized and systemic exposure or distribution to other organs or tissues has been demonstrated to be low.

For biotechnology-derived products that achieve highly specific receptor targeting, it is often sufficient to assess safety pharmacological endpoints as part of toxicology or pharmacodynamic studies, thus reducing or eliminating safety pharmacology studies for these products.

In addition, new salts with similar pharmacokinetics and pharmacodynamics and cytotoxic agents do not need to be tested for the treatment of patients with end-stage cancer.

However, extensive safety pharmacology studies should be considered for cytotoxic agents and biotechnology-derived products that represent new therapeutic classes or mechanisms of action or that do not achieve high receptor-specific targeting(Quoted from the Encyclopedia of Toxicology).

The research objectives of safety pharmacology include the following aspects: determine the undesired pharmacological effects of drugs that may be related to human safety; evaluate the adverse drug reactions and/or pathophysiological effects of drugs observed in toxicological and/or clinical studies ; The mechanism of adverse drug reactions observed and/or speculated in the research.

The basic principle

(1) Test method

The trial design should be rationally based on the characteristics of the drug and the purpose of clinical use. Choose appropriate and validated methods, including scientific and effective new technologies and new methods. Certain safety pharmacology studies can select test methods based on the model of pharmacodynamic response, the characteristics of pharmacokinetics, and the species of experimental animals. The test can use in vivo and/or in vitro methods.

(2) The phase of research

Safety pharmacology research runs through the entire process of new drug research and can be carried out in stages. Before the drug enters the clinical trial, the study of the core battery (Core Battery) test for the effects on the central nervous system, cardiovascular system and respiratory system should be completed. Additional and/or supplementary safety pharmacology studies can be completed before application for clinical or production, depending on the specific circumstances.

(3) Requirements for implementing GLP

Drug safety evaluation research must implement the “Non-clinical Drug Research Quality Management Practice” (GLP). In principle, safety pharmacology studies must perform GLP. For some special cases that are difficult to meet GLP requirements, proper test management and data storage must also be ensured. The core combination test shall perform GLP. Supplementary or/and supplementary safety pharmacology studies should follow GLP specifications as much as possible.

(4) Test substance

Traditional Chinese medicine and natural medicine: The test substance should be a sample that can fully represent the quality and safety of the samples to be used in clinical trials and/or the samples on the market. The process should be prepared after the process route and key process parameters are determined. Generally, it should be a sample of a pilot scale or above, otherwise there should be sufficient reasons. The name, source, batch number, content (or specification), storage conditions, expiration date and preparation method of the test substance should be indicated, and a quality inspection report should be provided. Due to the particularity of traditional Chinese medicines, it is recommended to use them now, otherwise data should be provided to support the quality stability and uniformity of the test substance after preparation. When the administration time is longer, it should be investigated whether the volume after preparation is swelled with the prolonged storage time, causing the final concentration to be inaccurate. If the volume or method of administration is limited, the drug substance can be used for testing. The solvent and/or auxiliary materials used in the test should be marked with the name, standard, batch number, expiration date, specification and production unit.
Chemical drugs: The test substance should be a sample with relatively stable technology, purity and impurity content that can reflect the quality and safety of the samples to be used in clinical trials and/or the samples on the market. The test substance should be marked with the name, source, batch number, content (or specification), storage conditions, expiration date and preparation method, etc., and a quality inspection report should be provided. The solvent and/or auxiliary materials used in the test should be marked with the name, standard, batch number, expiration date, specifications and production unit, etc., and meet the test requirements.
In the process of drug development, if the process of the test substance changes that may affect its safety, corresponding safety studies should be carried out.
During the chemical drug test, the test substance sample should be analyzed, and the sample analysis report should be provided. Traditional Chinese medicines and natural medicines with basically clear ingredients should also be analyzed for test substance samples.

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