What is toxicology
Toxicology is the study of the adverse effects of a chemical or biological agents on living organisms and the environement
What are the objectives of toxicology tests ?
1. Hazard / risk assessment
2. Determine the safe levels of exposure to natural and man-made chemicals
3. Contribute to the development of therapeutic agents
1. Why are preclinical toxicology tests a requirement ? what are we trying to show ?
2. Why do we perform toxicology tests prior to phase 3 clinical trials ?
1. Preclinical toxicology tests are a requirement to prove that the drug is safe prior to first administration to humans in clinical trials and also for later phase clinical trials aswell.
2. Usually patients with a disease tend to show more toxic response than healthy individuals.
What are the requirements of the regulatory authorities in terms of what does a preclinical stage should sponsor ?
1. To develop and demonstrate the pharmacological profile of the drug
2. Determine the acute toxicity of the drug
3. Conduct short term studies ranging from 2 weeks to 3 months depending on the proposed duration of the treatment by the substance
What is in summary the data that u must present in order to fulfill the requirements from the regulatory authorities.
Genomic Biomarker Analysis
CYP Screening Assay
In vitro Toxicity Mutagenicity
In vivo Toxicity
Understand the toxicological profile :
1. Characterise toxic effectsa in organs
2. Determine dose response
3. Establish a first safe dose level and dose range for human exposure
4. identify parameters for clinical monitoring of potential adverse effects
5. special toxicity
why do we need toxicity tests ?
Sulfanilamide 100 people died = diethylene gylcol
Aniline and aniline dyes were producing bladder tumours
German measles can lead to blindness deafness and death of offspring in pregnant women.
= 1938 Launch of FDA
Sedative with a good profile, prescribed for morning sickness
1960= phocomelia in babies of mothers who took the drug during the embryonic period.
THIS HAD a MAJOR IMPACT ON HOW DRUGS ARE TESTED TODAY EVEN MORE FOR TERATOLOGY INVESTIGATIONS.
Adverse drugs reactions ?
1. What is and ADR ?
2. What are the two types of ADR ?
1. ADRs are unwanted or harmful responses occuring at the therapeutic dose of the drug.
2. Type A : Pharmacological
Type B : idiosyncratic
What is a pharmacologic ADR ?
Predicted on known pharmacology
Common and dose related
Accounts for 80% of all the ADRs
Examples : Respiratory depression with opioids.
What is an idiosyncratic ADR
Unrelated to known pharmacology
example : Anaphylaxis with penicilin, bone marrow suppression with chloramphenicol.
Toxicokinetics ? what is it ?
Toxicokinetics is the quantitation of the time course of toxicants in the body
It is the sudy of what the body does to the drug in order to predict the concentration of toxin that reaches the site of injury and the damage it causes
What are the primary and secondary objectives of toxicokinetics ?
to describe the systemic exposure achieved in animals and the relationship to dose level and the time course of the toxicity study.
1. to relate the exposure found in the toxicity studies to toxicological findings and to extrapolate relevance for clinical safety
2. TO support the choice of species and treament regimen in non-clinical toxicity studies
3. To provide information which, in conjunction with the toxicity findings contribute to the design of the non-clinical studies.
Toxicokinetics and metabolites consideration ?
Metabolite could be a free radical