Pre-clinical studies

Pre-clinical studies

Content

•       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

Stages

•       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)

•       Free

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

–      Mandatory

–      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

•       Inhalational

•       Allergic studies

•       Rectal inflammation test

PK Studies

•       In several species

•       ADME

•       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

•       HED

Summary

•       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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