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What is Preclinical Safety Pharmacology Studies importance?

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Safety pharmacology, general toxicology, and special toxicology are the important contents of the non-clinical safety evaluation of drugs. In the early 21st century, the preclinical research of drug researchers mostly focused on the toxicity of lead compounds, but the adverse reactions of drugs in the early clinical stage were not observed. These adverse reactions are mainly concentrated in patients' central nervous system, cardiovascular system, respiratory system, and kidney system, so drug researchers began to take organ function tests as research content.

The research of Preclinical Safety Pharmacology Studies (Pharmacology) focuses on the adverse reactions of new drugs, and finding unexpected pharmacological effects, especially those reactions that are difficult to observe in subacute toxicity tests, can provide maximum guarantee for new drugs to enter the clinical research stage and go on the market.

Safety pharmacology studies described in ICH S7A and/or S7B should be performed to support expanded clinical studies or to support marketing approval for a botanical drug product, which can be divided into three categories: primary pharmacodynamics, secondary pharmacodynamics and safety pharmacology studies.

safety pharmacology 

Primary Pharmacology Studies

Investigate the mode of action and/or effects of a substance on its desired therapeutic target

Secondary Pharmacology Studies

Investigate the mode of action and/or effects of a substance not related to its desired therapeutic target

Safety Pharmacology Studies

Investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions to exposure in the therapeutic range and above

Safety pharmacology studies defined as those studies that investigate the potential undesirable pharmacodynamics effects of a substance on physiological functions in relation to exposure in the therapeutic range and above.

What is  Preclinical Safety Pharmacology Studies importance?

Safety pharmacology issues have a significant impact on CD attrition (both preclinically and during clinical development). Data are important for Phase I dose-setting. SP studies are a regulatory requirement for IND submissions before human exposure. There are 3 regulatory guidance documents focusing on safety pharmacology, and several others refer to it. The consequences of ‘getting it wrong can have dramatic implications.

The research of safety pharmacology is an indispensable part of the preclinical safety evaluation of drugs. The purpose of general pharmacology research is to find out the unexpected effects on organ function and find other pharmacological effects, while the research of safety pharmacology focuses on finding the adverse reactions of new drugs. Generally speaking, the importance of safety pharmacology research is mainly reflected in the following aspects.


(1)Identify the adverse pharmacodynamic characteristics of substances that may be related to human safety;

To observe the potential adverse effects of recombinant human interferon beta-1a injection on physiological functions and provide a basis and reference for clinical experiments, some drug developers have studied the effects of this drug on the central nervous system, respiratory system, cardiovascular system and digestive system of experimental animals.

The mice were treated with 5.5, 22.0, and 88.0μg/kg of recombinant human interferon β-1a injection, and the mice's independent activities were observed, and the balance and coordination ability and coordinated sleep experiments were carried out to study the effects of drugs on the central nervous system of animals. The cynomolgus monkeys were injected with recombinant human interferon β-1a at 1,4 and 16μg/kg in a single sc. The ECG, blood pressure, respiratory rate, and respiratory amplitude of cynomolgus monkeys were observed, and the effects of drugs on the animal's respiratory system and cardiovascular systems were studied. The mice were injected with recombinant human interferon β-1a at a dose of 5.5, 22.0, and 88.0μg/kg, and the gastrointestinal propulsion experiment was carried out to study the effect of drugs on the gastrointestinal digestive system.

Results in Recombinant human interferon β-1a injection had no obvious drug effects on the central nervous system, respiratory system, cardiovascular system, and digestive system of experimental animals.

(2)Evaluate adverse reactions and/or pathophysiological effects of drugs observed in drug toxicology and/or clinical studies;

For example, drug A is a traditional Chinese medicine prescription of cardiac glycosides, which has similar adverse reactions with cardiac glycosides, but is safer for clinical use.

Previous studies found that there was no adverse reaction during single administration, but abnormal ECG could be caused after repeated administration. Therefore, safety pharmacological tests of repeated administration were conducted, and ECG was taken as the endpoint index.

The researchers did not find any adverse reaction to the drug at the initial stage of administration, but the atrioventricular block appeared on ECG at 2 ~ 6h after the high dose group was administered at the later stage, which was consistent with the peak time of active substances in the body, and the organ distribution test showed that active substances could be detected in the heart, which once again confirmed that the target organ of the drug was the heart. Although there is no obvious accumulation of drugs in the body, Cmax and AUC in the high-dose group tend to increase with the administration time, and drugs can still be detected in the heart 24 hours after the last administration, suggesting that clinical long-term medication should pay more attention to cardiac indicators.

(3)Investigate the mechanism of observed and/or speculated adverse pharmacodynamic effects.

According to literature reports, some researchers have studied the effects of dexibuprofen injection on the central nervous system, cardiovascular system, and respiratory system of animals.

They examined the effects of dexibuprofen injection on the central nervous system by independent activity test, motor coordination test, and pentobarbital sodium hypnosis/sleep test in mice. The effects of dexibuprofen injection on the cardiovascular system and respiratory systems were investigated by detecting the telemetric ECG, blood pressure, and respiratory indexes of awake Beagle dogs.

The results showed that dexibuprofen injection had no significant effect on independent activities, motor coordination, cardiovascular system, and respiratory system, and had a synergistic effect with pentobarbital sodium in inducing hypnosis/sleep in mice at high doses.

In addition, by observing the effects of single and multiple intramuscular injections of biological product B on the cardiovascular system and respiratory system of conscious cynomolgus monkeys, including the nature, degree, dose-effect relationship, and time-effect relationship of the effects, the researchers determined the unobservable adverse reaction dose (NOAEL) of cardiovascular system and respiratory system safety pharmacological indicators, and explored the feasibility of carrying out safety pharmacology research in repeated toxicity tests.

Safety pharmacology studies can use in vivo and/or in vitro methods

What is In Vitro Safety Pharmacology Studies

In vitro studies should be designed to establish a concentration-effect relationship. The range of concentrations used should be selected to increase the likelihood of detecting an effect on the test system. The upper limit of this range may be influenced by Physico-chemical properties of the test substance and other assay-specific factors. In the absence of an effect, the range of concentrations selected should be justified.

Mode-of-Action (MoA) – In vitro cell studies to understand the compound Mode-of-Action. This can include antagonist/agonist characterization, signaling pathway analysis, binding characteristics, internalization of antibodies, and much more.

Functional Assays – Adequate assays to investigate the potency and efficacy of your compound, with a focus on human disease-relevant systems.

What is In Vivo Safety Pharmacology Studies

Safety pharmacology studies should be designed to define the dose-response relationship of the adverse effect observed.

The time course of the adverse effect should be investigated, when feasible. Generally, the doses eliciting the adverse effect should be compared to the doses eliciting the primary pharmacodynamic effect in the test species or the proposed therapeutic effect in humans, if feasible. It is recognized that there are species differences in pharmacodynamic sensitivity.

Customized Pharmacodynamics (PD) Models – A good PD model can provide pivotal information for understanding the efficacy, dose-response and time-effects of a drug. PD makers can often continue to serve as early target engagement biomarkers in man.

Pharmacokinetic (PK) Studies – We generate pharmacokinetic profiles in an individual animal, creating high robustness in your data. We can assist you with bioanalysis and ensure the best PK parameter determination using the industry-standard software Phoenix® WinNonlin®.

Modeling of PK/PD Relationships and Dose Predictions – A better understanding of the PK/PD relationship of your compound will provide key information for successful pre-clinical development and clinical design e.g. dose to man prediction etc.

Administration Routes and Proper Formulation – Delivery route and drug formulation is of key importance for success. We perform in vivo studies using most administration routes in rodents, including inhalation. Through close collaboration with formulation experts, we can ensure the optimal formulation of your drug.

Safety pharmacology is a rapidly developing new discipline. It has only been more than twenty years since ICH S7A was released in 2001, and there is still much room for development and progress. Pharmaceutical companies should be aware of the position of safety pharmacology in the safety evaluation of new drugs and adopt more advanced scientific and technological methods to research safety pharmacology, to provide valuable data for the later research and development of new drugs.

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