Chapter 9 - Toxicology Flashcards Preview

PHAR3006 Drug Design & Development > Chapter 9 - Toxicology > Flashcards

Flashcards in Chapter 9 - Toxicology Deck (13):

Are biologics species independent

No, small molecules are

Biologics are species specific


Are biologics long acting

Yes, small molecules are short acting


Do biologics exhibit toxicity?

No, small molecules do

Anitbodies exhibit exaggerated pharmacology


What are the 7 aims of toxicology studies?

1. Predict the likelihood to toxicity in humans
2. Identify target organs for toxicity HAZARD IDENTIFICATION
3. investigate reversibility of any toxic effects
4. Recommend a safe starting dose for phase I trials
5. Determine highest dose that can be safely administered to humans
6. Identify safety parameters for clinical monitoring RISK ASSESSMENT
7. Provide information on mechanism of action


what is researched in toxicology from target validation to lead isolation

review literature
-information on know-out phenotype or developmental expression and the function target and its related pathways
-early safety prediction (target liability, QSAR) teratogenicity

Review selectivity
-Receptor/ target binding data to identify potential side effects
-compound activity profiling (CEREP)
-tissue expression of target in animal species (mAbs)

Review CV alerts
-Dofetilide binding or electrophysiology for hERG liability
-screens for arrhythmogenic potential

Evaluation of chemical structure (SMs)
-alerts of genotoxicity (DEREK database), conduct preliminary generic toxicology studies
-repeat dose eat study at multiple levels


What can influence systemic exposure to biologics?

Anti-drug-Antibody clearance due to immunogenicity


What is researched in toxicology during lead candidate profiling?

Behavioural effects

Major organs - function

CV toxicity in non-clinical species is the major cause for early drug termination


What measures are taken for women of child bearing potential?

Usually excluded from phase I
Fertility study (rat) prior to phase II
Teratology in two species prior to phase II
Pre and post natal study (rat) prior to submission


What drugs have been shown to cause problems to women of child bearing potential

Thalidomide, acutane (teratogens)

ACE inhibitors - foetal death in late pregnancy


What measures are taken in paediatrics?

Postnatal development end points included in pre and post natal study
Juvenile animal toxicology studies


Give an example of a drug which causes problems to juveniles

Quinolone antibiotics
Known to cause arthropathy in juvenile animals but not adult


What should be particularly consider when testing reproductive toxicity of biologics?

Species selection.
In this, study design & dosing schedule, nature of the product & mechanism of action, immunogenicity, pharmacokinetics, and embryo-foetal exposure should be considered.


What guidelines are used for reproductive testing of biologics?

ICH S5(R2), ICH S6(R1), ICH S9, ICH M3(R2)