L21 & 22 Pharmacogenomics and clinical trials Flashcards
Individual variation def
in drug response refers to differences in response between individuals to the same dose of a drug
Intrinsic factors of ID variation
- Sex
- Age
- Pregnancy
- Disease
- Genetics
Extrinsic factors of ID variation
- Drug interactions
- Environment
- Diet
- Smoking
single nucleotide polymorphism -
substitution of one nucleotide with another
frequency < 1% in a population
Mutation
frequency > 1% in a population
Polymorphism
Coding region polymorphism changes what
Change protein activity
Regulatory region polymorphism changes what
Change amount of protein
N-acetyltransferase 2 (NAT2) is polymorphic will inhibit
Isoniazid (an anti-tuberculosis drug) is inactivated by acetylation by NAT2
Isoniazid
Slow acetylators
Intermediate acetylators
Fast acetylators
- slow acetylators (slow/slow) - hepatotoxicity & peripheral neuropathy
- intermediate acetylators (slow/fast)
- fast acetylators (fast/fast) - poor response because drug is quickly inactivated
Name 3 prodrugs
- Tenofovir Dispoxil
- Ciclesonide
- Azathioprine
Azathioprine metabolism
azathioprine (a prodrug)
↓
6-mercaptopurine
↓
thiouric acid (inactive) via xanthine oxidase
S-methyl-6-mercaptopurine (inactive) via thiopurine methyltransferase (TPMT)
6-thioguanine nucleotide (active)
TPMT
thiopurine methyltransferase
Clinical use of azathioprine -> (6-thioguanine nucleotide (active))
Can impair DNA synthesis in leukocyte precursors:
✔ stops production of malignant leukocytes → childhood leukaemia
✔ reduces production of normal leukocytes → inflammatory bowel disease
✔ fewer leukocytes to mediate transplant rejection (old use)
✖ stops production of normal leukocytes → cannot fight infection
pharmacogenetics and pharmacogenomics
importance
PCG:the effect of one single genetic variation &
genes that determine drug metabolism
PCGM: the effect of multiple genetic variations &
all genes that may determine drug response
Implementation into clinical practice challenges
- a perceived lack of clinical utility
- inability to access genotyping tests
- lack of clarity on cost-effectiveness
- lack of knowledge on how to interpret pharmacogenomic tests
- worries about disruption to the normal clinical pathway
- concerns over confidentiality issues
Different types of clinical trials
- Treatment trials
- Prevention trials
- Screening Trials
- Quality of life trials
Treatment trials
test new treatment, new combination of drugs or new approaches to surgery or radiation therapy (for people with a particular disease)
For clinical trials a drug must first prove itself in:
- in-vitro testing
- animal testing for activity and toxicity
A drug must be testing to see its safety and
- how effective it is in man
- what doses to use, by what route and how often
- effects of disease on response, drug interactions, etc?
Clinical trials are a sequence of human experiments aimed at fully revealing:
- Safety (= “tolerability” or “adverse events”)
- Efficacy
- Pharmacokinetics (Absorption, Distribution, Metabolism and Elimination:
ADME), interactions, etc
Clinical trials benefits
- New treatments may be better than those currently used
- Patients may be the first to benefit from new drugs
- Patients get high quality care
- patients can help others
Clinical trials risk
- New treatments are not always better that those currently used
- New treatments may have worse side effects
- Patients may have more doctor visits, procedure s or tests
- Some costs may not be covered by trial
Phase 1 of clinical trials: dose escalation
After extensive laboratory testing, the drug is tested in a small group of people, for the first time.
!-2 years and 20-100 ppl*
The aim of these trials is to find out:
* How safe the medicine is
* How it works
* How well it is tolerated
Phase 2 of clinical trials: Comparitive
Once a drug has been successfully trialled in a phase I study, it is then tested again in a small number of people who have the disease that the drug is being developed to treat.
1-2 years and 100-300 ppl
The aim of phase II trials is to assess the best dose of the drug in regard to its effectiveness and safety.
Phase 3 of clinical trials: Comparative but longer
When a phase II trial of a drug shows that the drug has potential benefits that outweigh the hazards (side effects), the drug is then tested in a phase III trial. Placebo and normal group
2-3 years and 1000-3000 ppl
The aim of phase III trials is to show that the new drug is:
* Effective for the treatment of a medical condition
* Safe to use
Phase 0
Around 10 ppl and takes 6-12 months - they are given a very low dose
FDA review and Phase 4
Fda or TDA needs to approve drug then is taken to the market where there is an observation phase. As general public takes drug they report any side effects to doctors that report it to others.
Phase 1. Find safe dose
- usually healthy volunteers
- very tight supervision
- careful dose escalation until first evidence
of toxicity
Phase 2. Might it work
- patients with condition
- participants usually selected with strict criteria
- relatively homogenous study population
- carefully monitored
- very good measures of treatment outcome
Phase 3. Does it work?
- Controlling bias
o use a comparator (often placebo or existing medication)
o allocate participants randomly to groups
o blind investigator and patient - Statistically powerful
o estimate variability in main outcome, decide how much benefit is worthwhile &
calculate the numbers of participants needed to properly test a statistical hypothesis
Phase 4. How safe?
- Collect adverse events on all who are prescribed the drug
- “Observational” Collect reports of “adverse events” in very big groups (measure
incidence, particularly events too rare to pick up in Phases 1 – 3
Placebos
- Tests efficacy of medical treatments
- Include inert tablets, inert injections, sham surgery,
“fake treatment” - Only approved when a placebo would not be
dangerous (ie when not best practice)
Best practice/comparative treatment
- Tests if medical treatments are better than current best practice
- unethical to use placebo
Blinding
- When participants do not know what they are taking
- When investigators do not know what the participant is taking (double blinding)
Clinical Study design - controls
Placebos
Best practice/comparative treatment
Blinding
Who carries out and governs drug trials?
slide
Sponsors
Investigators
Human Ethics ctte (HREC) for ethical ensurement
participants
Back to HREC then to regulatory authority to grant marketing licence
(HREC)
Human Research Ethics Committee
(HREC) Assesses clinical trials, from application to closure for:
Research merit and integrity: Soundly designed experiment
Justice: All participants have equal chance of benefit and harm
Beneficence: participant well-being has priority over all other considerations
Respect: participant’s wishes govern involvement
Clinical drug trial documents
Protocol
* Describes in detail an experiment meeting standards for:
o Ethical human research (NHMRC statement)
o Good Clinical Practice (ICH135/95)
Investigator’s Brochure
* All relevant pharmacology, as known at the time
Patient information and consent documents
* what will be required of the participant
* risks and benefits
* safe-guards for participant’s wellbeing, privacy, etc
* participant’s rights (withdrawal, etc)
