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
-information on know-out phenotype or developmental expression and the function target and its related pathways
-early safety prediction (target liability, QSAR) teratogenicity
-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?
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
Known to cause arthropathy in juvenile animals but not adult
What should be particularly consider when testing reproductive toxicity of biologics?
In this, study design & dosing schedule, nature of the product & mechanism of action, immunogenicity, pharmacokinetics, and embryo-foetal exposure should be considered.