Developing safe medicines

L1: Intro to the module

Safety assessment of medicines

- We will focus on medicines but environmental, agents, foods and industrial chemicals
can trigger adverse reactions in humans
- Essential component for drug discovery and development
- Specific studies at different stages of pipeline
- Supports earlier attrition and may prevent unnecessary clinical/animal
experimentation
- Saves time and money
- Allows risk:benefit ratio to be assessed to support licensing for patients

Every Drug is a Potential Poison

Drug discovery and development pathway

R&D pipeline and compound number

 1. Hypothesis- target (Need for the drug)
2. Target identification- (genomic studies, population- drug established for certain
genomic type, GWAS)
3. Target validation (in silico in vitro experiment- docking experiments to identify what
molecules bind and are effective on the target receptor- high throughput assay >
testing affinity)
4. Lead candidate- drug like properties (adding various groups increase solubility etc),
efficacy experiment (dose-response experiment- organ bath), safety ARDs- off target
effects (should have low affinity to off targets sites), in vivo experiments in other non-
human species
5. Regulated pre-clinic studies- safety pharmacology experiments in vivo, in vivo
toxicology, formulation (series of clinical trials- phase 1- healthy volunteers
(toxicology), phase 2- 20-100 small n. of patients (efficacy), phase 3- 1000-3000
large n. of patients

Development process
 Development
 Further chemistry synthesis and purification and formulation
 Efficacy screening e.g. animal models
 Pharmacokinetics
 Preclinical regulated safety testing ‘core battery’ and toxicology
 Phase 1 clinical trial + non clinical safety/toxicology
 Phase 2 clinical trial (efficacy) + non clinical safety/toxicology
  Phase 3 clinical trial (efficacy) + non clinical safety/toxicology
 Post marketing surveillance – ONGOING SAFETY
 Mistakes cost ££££££

Antihistamines; Meclizine

Dioxin, the short name for 2,3,7,8-tetrachlorodibenzo-para-dioxin (2,3,7,8-TCDD), is

considered to be one of the most dangerous compounds that pollute our environment. Its
chemical structure is made of two aromatic rings joined through a pair of oxygen atoms, as
shown in the above drawing

The first antiviral antisense oligodeoxynucleotides –

Safety assessment during drug development

- Safety testing occurs throughout the drug development process from early animal
efficacy studies through to clinical trials and post marketing surveillance.
- Non clinical =Experiments not undertaken in humans (e.g. lab animals, in vitro
assays)
- Pre clinical = Experiments conducted before the drug has ever gone in to humans

Development Programme for a New Drug

Q:
What if the adverse effect, such as a drug causing a lethal arrhythmia, occurs at a frequency
of 1:5000?
Will this be picked up in a Phase 3 trial? No, usually only upto 3000
When would it be picked up? Phase 4- Yellow card system, reported ARD post marketing

Understanding safety evaluation:

A list learning exercise?

No!!
There is no one-size fits all rule.
Appropriate and timely safety evaluation is determined by e.g.
- Risk:benefit (cancer vs. hayfever)
- Known adverse events related to compound class/target
- Target population (male/female/old/young?)
- Route of administration (oral, dermal, intravenous)
- Predicted use (acute - antibiotic vs. chronic - antihypertensive)
- Comorbidities (impaired renal function may alter PK, Css)
- Drug-drug interactions (will target pop. be likely to use other medication?)