Pre-clinical studies

Pre-clinical studies


       Stages of preclinical studies

       Pharmacodynamic studies

       Toxicity studies

       Assessment of safety index

Intended Learning Outcomes

At the end of this lecture, student will be able to

       Explain the stages of preclinical studies

       Outline pharmacodynamic studies

       Explain toxicity studies

       Discuss the assessment of safety index

Preclinical Studies


       Drug discovery (2-5 Years)

       Preclinical phase (1-2 Years)

       Clinical trial phase (5-7 Years)

       Regulatory approval (1-5 Years)

       Restricted marketing – PSUR (4 Years)


Major Areas of Preclinical Studies

PD studies

       Therapeutic use – studied in animals

       Pressure changes, ECG, ionotropic, chronotropic, CO, TPR

       Promising results: Cellular level - in vitro evidence for receptor activity

       Molecular level: For affinity, selectivity – Membrane fractions of tissues/ organs/ cultured cells

       Graded/ quantal assay to find ED50




Toxicological Studies

       Acute toxicity study

      To find out LD50

      Atleast 2 animal species, 2 routes

      In graded dose to many groups

·         Subacute toxicity study

      To find out target organ for susceptible toxicity

      2 animal species

      3 doses

      At maximum tolerated dose – 4 weeks to 3 months

       Chronic toxicity study

      If the drug is intended for chronic use

      2 animal species

      1-2 years duration

      Simultaneously with clinical trials

       Special toxicity


      Data on teratogenicity, mutagenicity, carcinogenicity

Special Toxicity Studies

a)      Effect on reproductive performance

       Sexual behavior, fertility, parturition, lactation

b)      Teratogenicity

       2 animal species (Rat and Rabbit)

       To study the effect of organogenesis

       Foetus – examined for skeletal/ visceral abnormality

c)        Carcinogenicity

       Drug: mutation, benign/ malignant tumor

       Low predictive power from animal test

       Unknown etiology of most spontaneous cancer

       Long latent period

       2 animal species

       Same dose as chronic toxicity for 2 years

     d)     Mutagenicity

       Abnormalities to genetic materials

       Permanent change to the hereditary constitution

       Mutation to reproductive cells: Defect in first generation progeny

d)      Local toxicity

       Dermal toxicity

       Dermal phototoxicity

       Vaginal toxicity

       Ocular toxicity


       Allergic studies

       Rectal inflammation test

PK Studies

       In several species


       Relative BA after oral / Parenteral

       Elimination t 1/2

Assessment of Safety index

       Toxicological studies and PD data

       LD50 / ED50

       Therapeutic index

       Safety factor

       Max. tolerated dose, No AEL dose



       Pharmacodynamic studies: Therapeutic use – studied in animals

       Toxicological studies

      Acute toxicity: Toxicity following single administration of high dose

      Chronic toxicity: Toxicity following chronic administration

       PK studies: ADME, Relative BA after oral / Parenteral

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