5. Pharmacogenetics And Pharmacogenomics

Question 1

1. To understand the uses of pharmacogenomic information in drug choice, monitoring and dosing (objective)

Answer 1

Answer later

Question 2

2. To understand how genetic polymorphisms can affect the pharmacokinetic and pharmacodynamic properties of a drug (objective)

Answer 2

Answer later

Question 3

3. To understand specific examples of pharmacogenetic differences and how they impact therapeutic and adverse drug responses (objective, see list below)

Answer 3

Answer later:

• Common cytochrome P450 polymorphisms and their effects on drug metabolism
• Isoniazid fast and slow acetylators
• Thiopurine methyltransferase and the use of purine analogs as anti-cancer agents
• Roles for glucose-6-phosphate dehydrogenase variants in drug-induced hemolysis

Question 4

Pharmacogenetics (definition)

Answer 4

Influence of genetic variability on drug responses (both therapeutic and toxic drug responses)

Question 5

Pharmacogenomics (definition)

Answer 5

Use of genetic information to predict drug responses

Question 6

Genetic differences may influence:

Answer 6

Pharmacokinetics of a drug: effects on ADME
Pharmacodynamics of a drug: effects on mediators of a drug’s action: both the direct target (receptor) with which the drug interacts and other processes (signal transduction pathways) that mediate a drug’s action

Question 7

Percentage of drugs influenced by actionable pharmacogenes

Answer 7

7% of FDA-approved medications are affected by actionable inherited pharmacogenes

18% of US outpatient prescriptions are affected by actionable germline pharmacogenomics

Question 8

Pharmacokinetic examples: Phase 1 Enzymes

Answer 8

CYP2D6

Cytochrome P450 2D6 responsible for metabolism of 20-25% of all medications

Metabolizes several classes of drugs:
Antidepressants, antiarrhythmics, B-adrenergic receptor antagonists and analgesics

Question 9

CYP2D6 Polymorphisms

Answer 9

Four phenotypes:

1. Poor metabolizers (PM)
2. Intermediate metabolizers (IM)
3. Extensive metabolizers (EM)
4. Ultrarapid metabolizers (UM)

Question 10

Effect of CYP2D6 genetic polymorphisms on survival of women with ER(+) breast cancer treated with tamoxifen

Answer 10

Tamoxifen used in treatment of estrogen receptor ER(+) tumors
Tamoxifen is a prodrug

Question 11

CYP2D6: nortripyline metabolism

Answer 11

Later

Question 12

CYP2D6: codeine

Answer 12

Later

Question 13

Additional consideration: drug interactions

Answer 13

Multiple drugs are CYP2D6 inhibitors

Classified as strong (fluoxetine, paroxetine), moderate (sertraline, duloxetine), and weak (buprenorphine)

Question 14

Pharmacokinetic examples: Phase II reactions

Answer 14

Isoniazid metabolism by NAT2 enzyme

Thiopurines metabolism

Question 15

Isoniazid Metabolism

Answer 15

Used for treatment of tuberculosis

Metabolized by N-acetyltransferase 2 (NAT2), a phase II enzyme

Question 16

Slow acetylators and Fast acetylators

Answer 16

Later

Question 17

Clinical Significance of Isoniazid Acetylation Rate

Answer 17

Influence of acetylation rate on the anti-tuberculosis activity is uncertain.

It does appear that the rate of acetylation influences isoniazid toxicity: slow acetylators are more prone to suffer from isoniazid toxicity, including peripheral neuropathy

Question 18

Metabolism of Thiopurines

Answer 18

• Used to treat autoimmune conditions (Crohn’s disease) and acute lymphoblastic leukemia and prevent organ transplant rejection
• Thiopurines include 6-mercaptopurine (6-MP) and azathioprine (AZA), have relatively low therapeutic index
• Neither 6-MP nor AZA has intrinsic activity, undergo biotransformations leading to formation of 6-thioguanine nucleotides (6-TGNs) that have cytotoxic effects and are incorporated into DNA
• Thiopurines inactivated by thiopurine S-methyltransferase (TPMT)

Question 19

Frequency distribution of red blood cell (RBC) thiopurine S-methyltransferase (TPMT) activity

Answer 19

20 variant alleles of TPMT

TPMT*2/3A/3C are defective alleles that encode for proteins with reduced catalytic activity

Question 20

Dosage Adjustment

Answer 20

Administration of standard doses of thiopurines to individuals with reduced or undetectable TPMT activity may produce life-threatening adverse events (myelosuppression, bleeding, severe infection). Need to reduce drug or use alternate drug.
Patients with high TPMT activity may display reduced response to standard doses of thiopurines and may require increased doses to get therapeutic response.

Question 21

Pharmacokinetic Examples: Other (not Phase I or II) Enzymes

Answer 21

Glucose 6-phosphate dehydrogenase

Question 22

Glucose 6-phosphate dehydrogenase

Answer 22

G6PD is rate-limiting step of PPP and role in maintaining NADPH and GSH levels
In RBC’s, G6PD is exclusive source of NADPH and GSH
If G6PD deficiency, at increased risk for hemolysis when exposed to oxidative stress (infection, fava beans, certain drugs) due to reduced antioxidant capacity

Question 23

G6PD

Answer 23

Deficiency, can develop haemolytic anaemia after eating broad beans or taking drug rasburicase.

Question 24

G6PD Deficiency

Answer 24

Defined as less than 60% activity

Question 25

G6PD Variants

Answer 25

Gene on X chromosome
180 genetic variants (90% single-base substitutions) for reduced catalytic activity
Hemizygous-deficient males and homozygous-deficient females express reduced activity phenotypes
Due to X-chromosome mosaicism, G6PD activity in cells from heterozygous females may range from fully functional to severly deficient

Question 26

Pharmacodynamic Examples

Answer 26

B2-adrenergic receptor polymorphisms

Gefitinib and EGFR mutations

Question 27

B2-adrenergic receptor polymorphisms influence bronchodilator response in asthma

Answer 27

B2AR agonists (albuterol) treat asthma
Two polymorphic loci in the coding region of receptor: Gly-16/Arg-16 and Glu-27/Gln-27
Children study:
Mutation in first loci children more likely to respond to albuterol
No association in second loci in response to albuterol

Question 28

Gefitinib and EGFR Mutations

Answer 28

Gefitinib is a tyrosine kinase (TK) inhibitor that targets the epidermal growth factor (EGF) receptor (used to treat non-small-cell lung cancer)

Most patients don’t respond to gefitinib, but 10% display rapid therapeutic response
High sensitivity due to somatic mutations clustered around ATP-binding pocket of EGFR TK domain.
Mutations associated with increased EGF-stimulated TK catalytic activity and increased sensitivity to gefitinib inhibition.

Question 29

Challenges in implementing pharmacogenomics

Answer 29

Need for means to compare adverse reactions associated with a drug across multiple studies

Imaging and biomarkers may help