Clinical trials and drug discovery Flashcards
What happens in basic research stage of drug development?
Target selection and lead finding
What is lead finding?
When the target is identified and the lead compounds are found
What happens in lead finding?
Cloning of target and then put into assay which will be tested with thousands of compounds in a companies library
Properties taken into account then selecting a lead molecule?
Lead molecule optimisation- improve target specificity, improve potency, pharmaceutical and pharmacokinetic properties, reduced safety liabilities
What happens in lead optimisation?
A broader range of assays are completed on different test systems, measure the activity and time course of compounds in vivo and check for unwanted effects in animals, evidence of genotoxicity and usually for oral absorption
Then a short list of lead molecules are optimised - ranked
What in vitro assays undergo in lead optimisation?
In vitro mutagenicity, clastogenicity and specific cardiac arrhythmia.
Also assays to screen for interference with bile salt export pump which may affect liver injury are more common now
What do in vitro mutagenicity test do?
Multiple strains of Salmonella engineered to be histidine deficient, those bacteria that are mutated back to have histidine are Ames positive- so may be carcinogenic
What do in vitro clastogenicity assays do?
Looks at gene mutations, chromosome aberration or breakage, and chromosome loss or gain
What, other than assays, are used in lead optimisation studies?
Overexpressed KO mouse - to obtain information on the intended target
Exploratory studies
What are exploratory studies for?
Identify unwanted toxicities evident after repeat administration for short duration as well as to identify putative toxicities based on a known cause of concern
What are benefits of exploratory studies?
Provide data to move the best candidate forward, allow to test for a specific cause of concern and can also provide data to help understand both on and off target toxicity
What is the difference between on and off target toxicity?
On- exaggerated and adverse pharmacological effects at the target of interest
Off- Refers to adverse effects as a result of modulation of the target
Goals of non clinical safety evaluations
Toxicity, toxicokinetics, max non toxic dose/ min effective dose, dose selection for first in human, identification of specific monitoring requirements
Aim of preclinical development
To satisfy all the requirements that have to be met before a new compound is deemed ready to be tested for the first time on humans
What is meant by good laboratory practice?
Formal operating code which aims to eliminate human error as far as possible in preclinical development
Why is GLP important in drug development?
To ensure reliability of the data submitted to the regulatory authority and labs are regularly monitor for compliance with the GLP
Applies to the non- clinical studies for the safety of man, animals and environment
What happens in preclinical development?
General toxicology- clinical pathology and pathology, Small molecules toxicology, safety pharmacology- undesirable effects on physiological functions e.g. CVS,CNS and respiratory
Genetic toxicology - in vitro and in vivo tests designed to detect compounds that induce genetic damage
Pharmacokinetics- drug metabolism
What are the similarities between small molecules and biopharmaceuticals?
Safety pharmacology, 1,3,6 month studies, developmental toxicology
What does small molecule pre clinical development have which biopharmaceutical do not?
14C ADME, max tolerated dose, t half short, toxic metabolites, Pk/PD correlation, genotoxicity, carcinogenicity
What do biopharmaceuticals pre clinical development have that small molecules don’t?
Tissue binding study, x target of saturation, t half long, immunogenicity, no PK/PD
What are different immunotherapies and how are they used to treat cancer?
Checkpoint inhibitors- natural brake on immune system so T cells attack tumours
CAR T cell Therapy (Chimeric Antigen Receptor)- genetically engineer a patients own immune cells to make a new protein
Cancer vaccine- train your body to protect itself against own damaged or abnormal cells
