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Safety pharmacology 1


Note: This document is summarizing from ICH guidelines.




The objectives of the preclinical safety studies are to define pharmacological and toxicological effects not only prior to initiation of human studies but throughout clinical development (Ref: ICH S6 (R1)).

Preclinical safety testing should consider:

1)      Selection of the relevant animal species;

2)      Age;

3)      Physiological state;

4)      The manner of delivery, including dose, route of administration, and treatment regimen; and

5)      Stability of the test material under the conditions of use (Ref: ICH S6(R1))

Important considerations for determining the nature of non-clinical studies and their timing with respect to clinical trials include:

a) duration and total exposure proposed in individual patients

b) characteristics of the drug (e.g. long half-life, biotechnology products)

c) disease or condition targeted for treatment

d) use in special populations (e.g. women of childbearing potential)

e) route of administration (Ref: ICH E8)



Order of studies:

     1. Animal Species:

Mouse > rat > hamster > other rodent > rabbit > dog > nonhuman primate > other nonrodent mammal > nonmammals

2. Route of Administration:

The intended route for human use > oral > intravenous > intramuscular > intraperitoneal > subcutaneous > inhalation > topical > other

3. Duration:Shortest duration first (Ref: ACTD Part III)



1) Safety Pharmacology (SP) (Ref: ICH S7 guideline)


  • Studies that investigate the potential undesirable pharmacodynamics (PD) effects on physiological functions in relation to exposure in the therapeutic range and above.
  • Pharmacology studies can be divided into three categories: primary pharmacodynamic, secondary pharmacodynamic and safety pharmacology studies.
  • Primary PD: studies on the mode of action and or effects in relation to the desired therapeutic target
  • Secondary PD: studies on the mode of action and/or effects not related to the desired therapeutic target
  • New chemical entities
  • Biotechnology-derived products
  • Marketed pharmaceuticals when appropriate (e.g., when adverse clinical events, a new patient population, or a new route of administration raises concerns not previously addressed).
Objectives of studies are:  
  • to identify undesirable PD properties of a substance that may have relevance to its human safety;
  • to evaluate adverse PD and/or pathophysiological effects of a substance observed in toxicology and/or clinical studies; and
  • to investigate the mechanism of the adverse PD effects observed and/or suspected.
General Considerations in Selection and Design of SP Studies: 
  • Effects related to the therapeutic class of the test substance, since the mechanism of action may suggest specific adverse effects (e.g., proarrhythmia is a common feature of antiarrhythmic agents);
  • Adverse effects associated with members of the chemical or therapeutic class, but independent of the primary PD effects (e.g., anti-psychotics and QT prolongation);
  • Ligand binding or enzyme assay data suggesting a potential for adverse effects;
  • Results from previous SP studies, from secondary PD studies, from toxicology studies, or from human use that warrant further investigation to establish and characterize the relevance of these findings to potential adverse effects in humans.
Test system:  
  • General Considerations
Selection factors can include the PD responsiveness of the model, pharmacokinetic (PK) profile, species, strain, gender and age of the experimental animals, the susceptibility, sensitivity, and reproducibility of the test system and available background data on the substance.
  • Use of In Vivo and In Vitro Studies
       -   Animal models as well as ex vivo and in vitro systems can include,
           but are not limited to: isolated organs and tissues, cell cultures, cellular
           fragments, subcellular organelles, receptors, ion channels, transporters
           and  enzymes.

     -    in vivo studies, it is preferable to use unanesthetized animals

  • Experimental Design

      -   Sample size: Adequate number of animals or isolated preparations

      -   Use of control: Negative and positive control groups

      -  Route of administration: Clinical route  If clinical use involves multiple routes
         of  administration (e.g. oral and parenteral), assessment of effects by more
         than one route may be appropriate
Dose Levels or Concentrations of Test Substance 
  • In Vivo Studies should be designed to define the dose-response relationship of the adverse effect observed. The time course (e.g., onset and duration of response) of the adverse effect should be investigated, when feasible.
  • 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.
Duration of Studies 
  • generally performed by single dose administration
  • consider repeat dose when:

     - PD effects occur only after a certain duration of treatment

     - Concerns from repeat dose nonclinical studies and human use

Studies on Metabolites, Isomers and Finished Products 
  • In vivo test system should be consider when major metabolites achieve systemic exposure in humans, major human metabolites are absent or at low concentration in animals, and metabolites from humans are known to substantially contribute to the pharmacological actions of the therapeutic agent. In vitro test systems can be used based on practical considerations.
  • In vitro or in vivo testing of the individual isomers should also be considered when the product contains an isomeric mixture.
  • Finished product formulation(s) should be conducted only for formulations that substantially alter the PK and/or PD of the active substance in comparison to formulations previously tested.
Safety Pharmacology Core Battery
  • Central Nervous System
  • Cardiovascular System
  • Respiratory System
Follow-up and Supplemental SP Studies Follow-up : Case-by case basis (core battery)Supplemental studies: other organ systems not addressed by core battery (renal / urinary system, autonomic nervous system, gastrointestinal system)
Timing of Safety Pharmacology Studies in Relation to Clinical Development
  • Prior to First Administration in Humans

          -   Core battery

          -   Any follow-up or supplemental studies identified as appropriate, based on a            cause for concern

  • During Clinical Development
         -   Additional studies may be warranted to clarify observed or suspected
             adverse effects in animals and humans
  • Before Approval

        -   Supplemental studies (if warranted)

Application of Good Laboratory Practice (GLP) 
  • Ordinarily GLP

       -    Core battery

       -    SP investigations can be part of toxicology studies

       -     Results of secondary PD studies may make a pivotal contribution to the safety evaluation for potential adverse effects in human

  • GLP to the greatest extent feasible
       -      Follow-up and supplemental studies
  • Not GLP

        -     Primary PD studies

        -    Secondary PD when not pivotal to safety


2) Exposure Assessment: Toxicokinetics and Pharmacokinetics (Ref: ICH S3A)





  • Toxicokinetics (TK) is defined as the generation of pharmacokinetic (PK) data, either as an integral component in the conduct of non-clinical toxicity studies or in specially designed supportive studies, in order to assess systemic exposure. These data may be used in the interpretation of toxicology findings and their relevance to clinical safety issues

  • Integration of pharmacokinetics into toxicity testing

  • PK data (adsorption, distribution, metabolism, excretion (ADME))


  • The primary objective of toxicokinetics is to describe the systemic exposure achieved in animals and its relationship to dose level and the time course of the toxicity study.

  • Secondary objectives are:

         -  To relate the exposure achieved in toxicity studies to toxicological
             findings and contribute to the assessment of the relevance of
             these findings to clinical safety.
         -  To support the choice of species and treatment regimen in non-clinical
             toxicity studies.
         -  To provide information which, in conjunction with the toxicity findings,
             contributes to the design of subsequent non-clinical toxicity studies.
  • PK measurements usually consist of plasma (or whole blood or serum) concentrations for the parent compound and/or metabolite(s) and should be selected on a case-by-case basis.  Plasma (or whole blood or serum) AUC, Cmax, C (time) and tmax are the most commonly used parameters in assessing exposure in toxicokinetics studies. Other measurements, for example urinary excretion, may be more appropriate for some compounds.  Other derived parameters, for example bioavailability, half-life, and fraction of unbound drug and volume of distribution may be of value in interpreting toxicokinetic data.

  • Toxicity studies may be usefully supported by toxicokinetic information includes single and repeated-dose toxicity studies, reproductive, genotoxicity and carcinogenicity studies.  Toxicokinetic information may also be of value in assessing the implications of a proposed change in the clinical route of administration.


Application of GLP

Must conform to GLP

Quantification of exposure

  • plasma (serum or blood) concentrations, or

  • the AUCs of parent compound and/or metabolite(s), or

  • tissue concentrations, or

  • the exposure and dose-dependence in humans at therapeutic dose levels (either expected or established), or

  • species differences (either qualitative or quantitative)

Timing of studies

Generally before phase III

Time points for sampling

As frequent as is necessary

Dose levels

  • Low dose levels

       -  preferably a no-toxic-effect dose level

  • Intermediate dose levels

  • High dose levels

Route of administration

Alternative routes of administration

Determination of metabolites

  • Studies should be conducted to support phase III clinical trials

  • Circumstances warranted to observe metabolite:

      -When the administered compound acts as a 'pro-drug' and
the delivered  metabolite is acknowledged to be the primary active          entity.
      -When the compound is metabolised to one or more pharmacologically or toxicologically active metabolites which could make a significant
contribution to tissue/organ responses.
      -When the administered compound is very extensively metabolised and the measurement of plasma or tissue concentrations of a major
metabolite is the only practical means of estimating exposure following administration of the compound in toxicity studies

Statistical evaluation of data

Mean or median values and estimates of variability

Analytical methods

The choice of analyte and the matrix to be assayed (biological fluids or tissue) should be stated and possible interference by endogenous components in each type of sample (from each species) should be investigated.  Plasma, serum or whole blood is normally the matrices of choice for toxicokinetic studies.

Toxicokinetics in the various areas of toxicity testing - specific aspects

Single-dose toxicity studies

  • Performed in a very early  phase of development

  • Plasma samples may be taken in such studies and stored for later analysis, if necessary; appropriate stability data for the analyte in the matrix sampled would then be required

  • Additional toxicokinetic studies may be carried out after completion of a single-dose toxicity study

  • Results: may help in the choice of formulation and in the prediction of rate and duration of exposure during a dosing interval.  This may assist in the selection of appropriate dose levels for use in later studies.

Repeated-dose toxicity studies

  • In vitro metabolic and plasma protein binding data for animals and humans and systematic exposure data in the species used should be evaluated before initiating human clinical trials.

  • TK studies may consist of exposure profiling or monitoring at appropriate dose levels at the start and towards the end of the treatment period of the first repeat dose study (for each species is normally of 14 days duration or longer).

Genotoxicity studies

  • For negative results of in vivo genotoxicity studies (have to demonstrated systemic exposure in the species used or to have characterised exposure in the indicator tissue)

Carcinogenicity (oncogenicity) studies

  • This guidance is on the need to estimate systemic exposure, to parent compound and/or metabolite(s) at appropriate dose levels and at various stages of an oncogenicity study

  • The treatment regimen, species and strain selection should, as far as is feasible, be determined with regard to the available pharmacokinetic and toxicokinetic information. 

  • In practice, the vast majority of these studies is conducted in the rat and mouse. 

  • A highest dose based on knowledge of probable systemic exposure in the test species and in humans may be an acceptable end-point in testing.

  • It is not considered essential to continue beyond six months

Reproductive toxicity studies

  • Fertility

  • Pregnant and lactating animals

  • Further information on pharmacokinetics in pregnant or lactating animals may be required depending on the results obtained.

  • Toxicokinetic monitoring in reproductive toxicity studies may be valuable in some instances, especially with compounds with low toxicity; such data are not generally needed for all compounds.


 3) Acute Toxicity Studies (Ref: ICH M3(R2), Q&A on the withdrawal of Note for guidance on single-dose toxicity)


  • Acute toxicity generally refers to adverse effects observed after a short time following administration (within 24 hours) of a single or multiple doses of a substance.
  • Traditionally, acute toxicity information has been obtained from single dose toxicity studies in two mammalian species using both clinical and parenteral route of administration, with the objective to determine the mode of death and a quantitative evaluation of the approximate lethal dose.
  • Lethality should not be an intended endpoint in study assessing acute toxicity
  • Information on the acute toxicity of pharmaceuticals agent could be useful to predict the consequence of human overdose situation and should be available to support phase III.
Organisation recommendation
  • The National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) and the Laboratory Animal Science Association (LASA)
4) Repeated-Dose Toxicity Studies (Ref: EMA Guideline on repeated dose toxicity)




  • Primary goal: to characterise the toxicological profile of the test compound following repeated administration.
  • Toxicity profile: MTD, NOAEL


General Principles

  • Must conform to GLP
  • The design of the study should be based on available PK, PD and toxicological information

General Recommendations On Substance Quality

  • physicochemical characteristics
  • stability data

General Recommendations Concerning the experimental


  • Animal species: Based on their similarity to humans with regard to pharmacokinetic profile (responsive to the primary pharmacodynamic effect of the substance)
  • Sexes: Normally, equal numbers of male and female animals should be used
  • Size of treatment groups: Sufficient based on background knowledge
  • Number of species: two mammalian species (one non-rodent)
  • Animal husbandry: High standard (controlled of environmental conditions, diet and water quality and composition)

General Recommendations Concerning Dose And


  • Duration of administration: equal to or exceed the duration of the proposed therapeutic use
  • Route of administration: same route as that intended for humans
  • Frequency of administration: case-by-case basis
  • Dose levels: In general, the treatment should include:

-   Appropriate control group(s); in special cases a positive control group may be necessary for example in toxicology studies with special biological end-points (e.g., genotoxicity).

-   A low dose, sufficient to produce a pharmacodynamic effect or the desired therapeutic effect, or result in systemic exposure comparable with that expected at the intended clinical use

-  A high dose, selected to enable identification of target organ toxicity or other non-specific toxicity, or until limited by volume of dose. Limit doses for acute, subchronic, and chronic toxicity studies of 1000 mg/kg/day for rodents and non-rodents are considered appropriate in all cases except those discussed in the Guideline ICH M3 (R2).

-    An intermediate dose, such as the geometric mean between the high and the low dose.


  • Pre-treatment and control values:

-   for both rodents and non-rodents, historical control data should be available for the morphological, biochemical and physiological variables studied.

-  In the case of non-rodents, pre-treatment values should be obtained from the animals used in the study.

  • Monitoring during the study: food intake, general behaviour, body weight, haematological parameters, clinical chemistry, urinalysis and ophthalmology. Electrocardiographic recordings should be obtained in non-rodent species.
  • Toxicokinetics: Information on systemic exposure of animals
  • Terminal monitoring:

-  Autopsy must be conducted on all animals (histopathology or histologically)


 5) Genotoxicity Studies (Ref: ICH S2 (R1))


  • Purpose: to optimize the standard genetic toxicology battery for prediction of potential human risks, and to provide guidance on interpretation of results (gene mutaions. Structural chromosome aberrations and numerical chromosome aberrations (polyploidy, aneuploidy), with the ultimate goal of improving risk characterization for carcinogenic effects that have their basis in changes in the genetic material. 
  • Recommended protocol: Organization for Economic Co-operation and Development (OECD) guidelines and the reports from the International Workshops on Genotoxicity Testing (IWGT)
  • Scope: The focus of this guidance is testing of new “small molecule” drug substances, and the guidance does not apply to biologics.
Standard test battery
  1. Assessment of mutagenicity in a bacterial reverse gene mutationThis test has been shown to detect relevant genetic changes and the majority of genotoxic rodent and human carcinogens.
  2. Genotoxicity should also be evaluated in mammalian cells in vitro and/or in vivo as follows.
 Description of the Two Options for the Standard Battery
  1. Option 1
  • A test for gene mutation in bacteria.
  • A cytogenetic test for chromosomal damage (the in vitro metaphase chromosome aberration test or in vitro micronucleus test), or an in vitro mouse lymphoma Tk gene mutation assay.
  • An in vivo test for genotoxicity, generally a test for chromosomal damage using rodent hematopoietic cells, either for micronuclei or for chromosomal aberrations in metaphase cells.
  1. Option 2
  • A test for gene mutation in bacteria.
  • An in vivo assessment of genotoxicity with two different tissues, usually an assay for micronuclei using rodent hematopoietic cells and a second in vivo assay.  Typically this would be a DNA strand breakage assay in liver, unless otherwise justified
Recommendations for in vitro tests
  • Test Repetition:  not usually warranted
  • Interpretation: clearly negative or clearly positive, or equivocal
  • Test Protocol:

         -          Bacterial Mutation Assay: a single bacterial mutation (Ames) test

       -          Mammalian Cell Assays: in vitro cytogenetic assays

Recommendations for in vivo tests
  • Tests for the Detection of Chromosome Damage In Vivo: analysis of chromosomal aberrations or the measurement of micronucleated polychromatic erythrocytes in bone marrow cells in vivo
  • Other test: the DNA strand break assays and alkaline elution assay, the in vivo transgenic mouse mutation assays and DNA covalent binding assays, and the liver unscheduled DNA synthesis (UDS) assay
  • Dose Selection: Short-Term Studies, Multiple Administration Studies, Testing Compounds that are Toxic for Blood or Bone Marrow
  • Number of Animals Analysed: randomly selected from the group used for the toxicology study
  • Use of Male/Female Rodents: Acute protocol (only one sex), Acute tests (both sexes)
  • Route of Administration: generally the expected clinical route, e.g., oral, intravenous or subcutaneous, but can be modified if appropriate in order to obtain systemic exposure, e.g., for topically applied compounds
  • Control: positive control only periodically, and not concurrently with every assay



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