Pharmacogenomics

Question 1

What type of resource is PharmGKB?

Answer 1

Takes available evidence (ex. journal articles) outlining relationships between genetic variation and variable drug responses

Question 2

What type of resource is PharmVar?

Answer 2

Repository for allelic variation (and haplotype structure) for genes important for pharmacogenomics

Question 3

What type of resource is Clinical Pharmacogenetics Implementation Consortium (CPIC)? Also, name 2 other guideline groups

Answer 3

Translates available genetic information into therapeutic decisions through production of clinical practice guidelines

1. Dutch Pharmacogenetics Working Group (DPWG)
2. Canadian Pharmacogenomics Network for Drug Safety (CPNDS)

Question 4

5 examples of drugs with genetic variation influencing pharmacokinetics

Answer 4

1. CYP2C9 (drug-metabolizing enzyme) - warfarin
2. CYP2D6 (drug-metabolizing enzyme) - codeine
3. TPMT/NUDT15 (drug-metabolizing enzyme) - azathioprine (aka 6-mercaptopurine)
4. SLCO1B1 (drug transporters) - Simvastatin

Question 5

What are prodrugs?

Answer 5

Poor metabolizers that have a dec. risk of adverse drug rxns but an incd. risk of treatment failure (ie. nonreponse)

Ex. codeine, bioactivated by CYP2D6

Question 6

What are active drugs?

Answer 6

Poor metabolizers that have an incd. risk of adverse drug rxns that’s typically accompanied by incd. (or excessive) response to treatment

Ex. azathioprine and 6-mercaptopurine, inactivated by TPMT

Question 7

What are 3 characteristics of codeine and CYP2D6?
(gene, phenotype, therapeutic change)

Answer 7

1. Gene: CPY2D6; involved in codeine metabolism/bioactivation
2. Phenotype: different levels of morphine (pain relief) in different metabolizers
3. Therapeutic change: personalized dosing

Question 8

How does codeine impact pharmacokinetics?

Answer 8

It is a prodrug that requires drug metabolism for therapeutic effect (bioactivated by CYP2D6). The codeine therapeutic recommendation can be made based on metabolizer status (ie. CYP2D6 phenotype)

Question 9

What are 3 characteristics of azathioprine (6-mercaptopurine) and TPMT?

(gene, indication, and variation)

Answer 9

1. Gene: TPMT; involved in drug metabolism/inactivation
2. Indication: used to treat nonmalignant immunologic disorders and lymphoid malignancies
3. Variation: TPMT loss-of-function single nucleotide variants are relatively common (ex. *2, *3A, *3B, *3C)

Question 10

How is azathioprine (6-mercaptopurine) pharmacokinetics influenced by genetic variation in TPMT?

Answer 10

Azathioprine (6-mercaptopurine) is an example of an active drug requiring drug metabolism to stop therapeutic effect (inactivated by TPMT)

TPMT is required for drug inactivation -> TMPT LOF alleled leads to reduced inactivation -> incd. 6-thioguanine nucleotide exposure -> incd. risk of toxicity

Question 11

How is azathioprine (6-mercaptopurine) pharmacokinetics influenced by genetic variation in NUDT15?

Answer 11

NUDT15 is involved in metabolizing toxic 6-thioguanine (6-TGN) nucleotides -> NUDT15 LOF alleles results in reduced metabolism -> incd. 6-TGN exposure -> incd. risk of toxicity

Question 12

What are 3 characteristics of azathioprine (6-mercaptopurine) and TPMT/NUDT15?

(phenotype, implications, and therapeutic change)

Answer 12

1. Phenotype: different levels of the active drug for different metabolizers
2. Implications: patients with LOF alleles only tolerate lower doses and are at highest risk of bone marrow toxicity
3. Therapeutic change: personalized dosing with lower doses recommended for carriers of LOF variation

Question 13

What are 6 characteristics of simvastatin and SLCO1B1?

(indication, gene, variation, phenotype, implication, therapeutic change)

Answer 13

1. Indication: used for cholesterol reduction
2. Gene: SLCO1B1 (drug transporter responsible for the hepatic uptake, and subsequent elimination, of statins)
3. Variation: the most common LOF variant is SLCO1B1*5 that reduces transporter activity
4. Phenotype: differences in drug exposure between patients
5. Implications: patients with LOF variants (SLCO1B1*5) have incd myopathy b/c of incd drug exposure
6. Therapeutic change: SLCO1B1*5 carriers should consdier lower doses, alternative statins, or incd monitoring

Question 14

How is simvastatin pharmacokinetics influenced by genetic variation in SLCO1B1?

Answer 14

SLCO1B1 is required for drug elimination -> SLCO1B1*5 reduces transport/elimination -> incd. statin exposure -> incd. myopathy risk

Question 15

3 examples of drugs with genetic variation influencing pharmacodynamics

Answer 15

1. HLA-B (off-target effects) - carbamazepine
2. IFNL3/IL18B; IFNL4 (part of disease mechanism) - interferon/hepatitis C drugs
3. VKORC1 (drug target) - warfarin

Question 16

3 characteristics of VKORC1 and warfarin

(indication, gene, variation)

Answer 16

1. Indication: used as an anticoagulant (treatment of blood clots)
2. Gene: VKORC1 (the target enzyme of warfarin that participates in vitamin K recycling)
3. Variation: a common reduction-of-function variant that exists that leads to decreased dose requirements

Question 17

3 characteristics of IFNL4 and hepatitis C drugs

(indication, gene, variation)

Answer 17

1. Indication: used for viral eradication
2. Gene: IFNL4 plays a role in the immune response to the virus
3. Variation: leads to activation of the IFNL4 that leads to an overactive immune response and increased risk of treatment failure

Question 18

MOA of IFNL4 variant and hepatitis C drugs - why is an overactive immune system response to the virus bad?

Answer 18

rs1297860 is linked to an insertion variant that activates the IFNL4 pseudogene -> overactive immune response to the virus -> promotes the generation of viral genetic variants more resistant to antiviral treatment

Question 19

How does IFNL4 and hepatitis C drugs affect phenotype, implications, and therapeutic change?

Answer 19

Phenotype: variability in antiviral drug effectiveness on different patients

Implications: patients with the IFNL4 variant have a higher risk of treatment failure (and need for a re-treatment)

Therapeutic change: more effective antivirals could be considered in patients carrying IFNL variants

Question 20

3 characteristics of HLA variants and carbamazepine

(indication, genes, and variation)

Answer 20

1. Indication: used as an anticonvulsant
2. Genes: HLA-A and HLA-B are genes that present intracellular antigens to the immune system
3. Variation: indivs. carrying HLA-B15:02 and HLA31:01 variation are at increased risk of severe skin reactions

Question 21

What are the notations for the HLA gene variants?

Answer 21

Carriers are denoted as positive for the risk alleles, and non-carriers are negative for the risk alleles

Question 22

How does HLA variants and carbamazepine affect phenotype, implications, and therapeutic change?

Answer 22

Phenotype: the variants are necessary, but not sufficient for the development of severe skin reactions

Implications: patients positive for the risk alleles are at incd. risk for severe skin reactions

Therapeutic change: patients positive for the risk alleles are recommended to use a different drug if possible

Question 22

What are 2 possible ways to incorporate pharmacogenetic information into clinical decisions?

Answer 22

1. Pharmacogenetic testing performed only when a specific drug is being considered
2. Comprehensive pharmacogenomic information collected and made readily available for the future

Question 23

What is the strength and weakness of pharmacogenetic testing performed only when a specific drug is being considered?

Answer 23

Strength: assessing only variants with clinical relevance allows for rapid evidence-informed treatment decisions

Weakness: requires quick turnaround time, integration of pharmacogenetics testing into clinic flow, and pharmacogenomics training for care providers

Question 24

What is the strength and weakness of comprehensive pharmacogenomic information collected and made readily available for the future?

Answer 24

Strength: care providers can receive notifications for safety and effectiveness concerns for any drug considered over a patient's lifetime (where genetic info is embedded in electronic health records) Weakness: required curated and regularly-updated pharmacogenomic info to guide treatment decisions