L21 & 22 Pharmacogenomics and clinical trials

Question 1

Individual variation def

Answer 1

in drug response refers to differences in response between individuals to the same dose of a drug

Question 2

Intrinsic factors of ID variation

Answer 2

• Sex
• Age
• Pregnancy
• Disease
• Genetics

Question 3

Extrinsic factors of ID variation

Answer 3

• Drug interactions
• Environment
• Diet
• Smoking

Question 4

single nucleotide polymorphism -

Answer 4

substitution of one nucleotide with another

Question 5

frequency < 1% in a population

Answer 5

Mutation

Question 6

frequency > 1% in a population

Answer 6

Polymorphism

Question 7

Coding region polymorphism changes what

Answer 7

Change protein activity

Question 8

Regulatory region polymorphism changes what

Answer 8

Change amount of protein

Question 9

N-acetyltransferase 2 (NAT2) is polymorphic will inhibit

Answer 9

Isoniazid (an anti-tuberculosis drug) is inactivated by acetylation by NAT2

Question 10

Isoniazid
Slow acetylators
Intermediate acetylators
Fast acetylators

Answer 10

• slow acetylators (slow/slow) - hepatotoxicity & peripheral neuropathy
• intermediate acetylators (slow/fast)
• fast acetylators (fast/fast) - poor response because drug is quickly inactivated

Question 11

Name 3 prodrugs

Answer 11

1. Tenofovir Dispoxil
2. Ciclesonide
3. Azathioprine

Question 12

Azathioprine metabolism

Answer 12

azathioprine (a prodrug)
↓
6-mercaptopurine
↓
thiouric acid (inactive) via xanthine oxidase
S-methyl-6-mercaptopurine (inactive) via thiopurine methyltransferase (TPMT)
6-thioguanine nucleotide (active)

Question 13

TPMT

Answer 13

thiopurine methyltransferase

Question 14

Clinical use of azathioprine -> (6-thioguanine nucleotide (active))

Answer 14

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

Question 15

pharmacogenetics and pharmacogenomics
importance

Answer 15

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

Question 16

Implementation into clinical practice challenges

Answer 16

• 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

Question 17

Different types of clinical trials

Answer 17

• Treatment trials
• Prevention trials
• Screening Trials
• Quality of life trials

Question 18

Treatment trials

Answer 18

test new treatment, new combination of drugs or new approaches to surgery or radiation therapy (for people with a particular disease)

Question 19

For clinical trials a drug must first prove itself in:

Answer 19

• in-vitro testing
• animal testing for activity and toxicity

Question 20

A drug must be testing to see its safety and

Answer 20

• how effective it is in man
• what doses to use, by what route and how often
• effects of disease on response, drug interactions, etc?

Question 21

Clinical trials are a sequence of human experiments aimed at fully revealing:

Answer 21

• Safety (= “tolerability” or “adverse events”)
• Efficacy
• Pharmacokinetics (Absorption, Distribution, Metabolism and Elimination:
  ADME), interactions, etc

Question 22

Clinical trials benefits

Answer 22

• 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

Question 23

Clinical trials risk

Answer 23

• 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

Question 24

Phase 1 of clinical trials: dose escalation

Answer 24

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

Question 25

Phase 2 of clinical trials: Comparitive

Answer 25

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.

Question 26

Phase 3 of clinical trials: Comparative but longer

Answer 26

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

Question 27

Phase 0

Answer 27

Around 10 ppl and takes 6-12 months - they are given a very low dose

Question 28

FDA review and Phase 4

Answer 28

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.

Question 29

Phase 1. Find safe dose

Answer 29

* usually healthy volunteers * very tight supervision * careful dose escalation until first evidence of toxicity

Question 30

Phase 2. Might it work

Answer 30

* patients with condition * participants usually selected with strict criteria * relatively homogenous study population * carefully monitored * very good measures of treatment outcome

Question 31

Phase 3. Does it work?

Answer 31

* 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

Question 32

Phase 4. How safe?

Answer 32

* 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

Question 33

Placebos

Answer 33

* 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)

Question 34

Best practice/comparative treatment

Answer 34

* Tests if medical treatments are better than current best practice * unethical to use placebo

Question 35

Blinding

Answer 35

* When participants do not know what they are taking * When investigators do not know what the participant is taking (double blinding)

Question 36

Clinical Study design - controls

Answer 36

Placebos Best practice/comparative treatment Blinding

Question 37

Who carries out and governs drug trials?

Answer 37

**slide** Sponsors Investigators Human Ethics ctte (HREC) for ethical ensurement participants Back to HREC then to regulatory authority to grant marketing licence

Question 38

(HREC)

Answer 38

Human Research Ethics Committee

Question 39

(HREC) Assesses clinical trials, from application to closure for:

Answer 39

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

Question 40

Clinical drug trial documents

Answer 40

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)