Pharmacogenomics

Question 1

Describe how genetic polymorphisms in drug metabolizing enzymes can affect standard drug metabolism, serum concentration, efficacy, and toxicity. How do you adjust clinically?

Answer 1

POOR METABOLIZERS (VAR/VAR)

• decreased metabolism
• increased serum concentration of active drug
• increased efficacy
• increased potential for toxicity
• clinical: lower dose, alternative

ULTRA RAPID METABOLIZERS (WT/MC)

• increased metabolism
• decreased serum concentration of active drug
• decreased efficacy
• decreased potential for toxicity
• clinical: higher dose, alternative

Question 2

Describe how polymorphisms in drug transporter proteins can contribute to drug response variabilities.

Answer 2

DECREASED INFLUX ACTIVITY

• reduced uptake
• decreased efficacy
• if liver: elimination decreased
• potential for toxicity in “off target” tissues

DECREASED EFFLUX ACTIVITY

• reduced excretion
• increased efficacy
• increased toxicity
• decreased elimination
• compromised BBB

Question 3

Describe how polymorphisms in drug target proteins contribute to drug response variability.

Answer 3

Ex1: reduced copies of promoters => do not respond to drug

Ex2: SNPs in B1 receptors cause downregulation or reduction in GPCRs => do not respond as well

Ex3: polymorphism in downstream signaling molecule => enhanced response to SSRIs => better outcomes

Question 4

Describe how polymorphisms in VKORC1 contribute to variability in the response to warfarin.

Answer 4

VKORC1 is direct target of warfarin

• -1639G promoter region => higher VKOR => higher dose
• -1639A promoter region => lower VKOR => lower dose (90% of asians)
• rare mutation => reduced affinity of warfarin for VKOR => high dose

Question 5

Discuss the different mechanisms by which genetic polymorphisms can contribute towards drug-induced adverse effects.

Answer 5

PK-BASED
- polymorphisms in metabolizing enzymes or drug transporters leading to increased serum levels and toxicity (ex: 2C93 and warfarin => bleeding, OATP1B15 and statins => myopathy)

PD-BASED
- polymorphisms in drug targets (VKORC1 and warfarin)

IDIOSYNCRATIC DRUG-INDUCED HEPATOTOXICITY
- most common reason for failed clinical trials and drug recalls

IDIOSYNCRATIC DRUG-INDUCED HYPERSENSITIVITY

• often life-threatening allergic reactions
• FDA recommends genetic screening for asians to prevent steven johnson syndrom

Question 6

List some of the current barriers to full implementation of pharmacogenetics into clinical practice.

Answer 6

• physician education
• not enough data
• alternative medications
• cost effectiveness
• timeliness
• insurance
• lack of clear clinical guidelines

Question 7

Define targeted therapy and explain how pharmacogenetic data is used in therapeutic decision making.

Answer 7

• typically used in cancers by identifying specific biomarkers
• ex: herceptin for tumors overexpressing Her2

Question 8

Contrast polymorphisms in CYP3A4 vs CYP2D6, 2C19, and 2C9.

Answer 8

CYP2D6, 2C9, 2C19

• very polymorphic
• significant variations
• clinically significant

CYP3A4

• rare polymorphic alleles
• little variation
• redundancy with CYP3A5
• not significant

Question 9

Describe the clinical relevance of CYP2C9 polymorphisms with regards to warfarin.

Answer 9

Warfarin is given as a prodrug. CYP2C9 is responsible for inactivating the active S-warfarin. Those with 2C92/3 polymorphisms have decreased metabolism =>

• increased concentration of active warfarin
• bleeding events
• requires lower dosing

Those with CYP2C915/25 polymorphisms are null.

Question 10

Describe the clinical relevance of CYP2C9 polymorphisms with regards to warfarin.

Answer 10

Warfarin is given as a prodrug. CYP2C9 is responsible for inactivating the active S-warfarin. Those with 2C92/3 polymorphisms have decreased metabolism =>

• increased concentration of active warfarin
• bleeding events
• requires lower dosing

Those with CYP2C915/25 polymorphisms are null.

Question 11

Describe effects of polymorphisms in Phase II enzymes.

Answer 11

• decreased elimination

- increased risk for toxicity

Question 12

Describe genetic polymorphisms of OATP1B1 drug transporter.

Answer 12

OATP1B15/15

• decreased hepatic uptake of statins
• reduced efficacy
• increased serum concentration
• increased toxicity/accumulation in muscles
• clinical: reduced dose