Pharmacogenomics (Anderson's lectures)

Question 1

CYP2C19 IM relative frequency?

Answer 1

*2 is most common, but also *3 - *8
Reduced metabolism
Asian
Caucasian

Question 2

CYP2C19 UM relative frequency?

Answer 2

*17
Ultra rapid metabolizer
Black
White
Heterozygous most common

Question 3

CYP2C9 IM relative frequency?

Answer 3

*2
Reduced activity (70%)
Caucasian

Question 4

CYP2C9 PM relative frequency?

Answer 4

*3
Little activity (2-5%)
Caucasian

Question 5

CYP2D6 UM relative frequency

Answer 5

Multiple copies of *1, *2
Hyper-functional
Ethiopan, Saudi Arabian

Question 6

CYP2D6: IM relative frequency

Answer 6

9, 10, *17
(or can be heterozygous for *1)
Asian (10)
Black (17)

Question 7

CYP2D6: PM relative frequency

Answer 7

*3 - *6 (loss of function)

White

Question 8

How does gene-dose effect relate to clopidogrel metabolism?

Answer 8

PM/IM have a higher chance of a fatal CV event (not converted to the active form - remember, it’s a prodrug)
UM: greater risk of bleeding, but better outcome overall

Question 9

How does gene-dose effect relate to es/citalopram metabolism?

Answer 9

PM have a higher risk of QT prolongation, cardiotoxicity

Question 10

How does the number of NAT2*4 (rapid metabolizer) genes influence isoniazid dosing?

Answer 10

The presence of 1 allele drops the dose (normally 7.5 mg/kg/day) by 2.5 mg/kg for each allele.

Question 11

Per CPIC, which groups have recommended changes in clopidogrel?

Answer 11

IM/PM: have reduced platelet inhibition and more platelet aggregation –> increased risk of CV events. Use an alt. and genotype anyone undergoing PCI

Question 12

Per CPIC, which groups have recommended changes in es/citalopram and why?

Answer 12

UM: increased metabolism, lower plasma concentration –> treatment failure. Use an alt.
PM: reduced metabolism and high plasma concentration –> adverse reaction. Consider 50% dose reduction, titrate. Or use an alt.

Question 13

What are some moderate inhibitors of CYP2D6?

Answer 13

Cimetidine
Duloxetine
Fluvoxamine
Sertraline

Question 14

What are some strong inhibitors of CYP2D6?

Answer 14

Buproprion
Fluoxetine
Paroxetine
Quinidine

Question 15

What are substrates CYP2C19?

Answer 15

PPI's
Clopidogrel
Sertraline
Es/citalopram
Amitryptyline

Question 16

What are substrates of CYP2C9 that we talked about in class?

Answer 16

S-warfarin

Phenytoin

Question 17

What are substrates of CYP2D6 that we talked about in class?

Answer 17

Codeine, tamoxifen

Also other pain meds, beta blockers, haloperidol, risperidone

Question 18

What are the dose changes for tamoxifen recommended by CPIC?

Answer 18

PM: use alt
IM: higher dose, avoid ANY inhibitors
EM/UM: normal dose, avoid strong/moderate inhibitors

Question 19

What factors would make us decrease the dose of warfarin?

Answer 19

Age
VKORC1 allele (28% per each)
Drugs like amiodarone
*2 or *3 allele (19 - 33%)

Question 20

What factors would make us increase the dose of warfarin?

Answer 20

Target INR
BSA
Current thrombosis

Question 21

Abacavir HLA allele

Answer 21

HLA-B*5701

Increased likelihood of drug related hypersensitivity

Question 22

Phenytoin HLA allele

Answer 22

HLA-B:15:02 (weak evidence that it can cause SJS/TEN).
Not having this allele doesn’t rule out this reaction.
CYP2C9 is the major path. *3 genotype associated w/ SJS/TEN

Question 23

Abacavir recommendation

Answer 23

Screen all naive patients before starting therapy.

If a carrier, avoid use and use alt.

Question 24

Allopurinol recommendation

Answer 24

Contraindicated if positive for *58:01.

Consider genotyping in Han Chinese/Thai, or if Korean with CKD stage 3 or worse.

Question 25

What is the dose change of warfarin for a CYP2C9 *2 (intermediate activity)?

Answer 25

Drop the dose by 19% per allele

Question 26

What is the dose change of warfarin for a CYP2C9 *3 (poor activity)?

Answer 26

Drop the dose by 33% per allele

Question 27

What is the frequency of NAT2 rapid acetylators?

Answer 27

Highest in Vietnamese, Japanese, Chinese

Question 28

What is the frequency of NAT2 slow acetylators?

Answer 28

Most in white and black

Question 29

What is the frequency of the VKORC1 variant?

Answer 29

Asian 90% | White 40%

Question 30

What is the gene-dose effect?

Answer 30

Some medications do not need genotyping because you can titrate to effect. Not 100% of the time, though.

Question 31

Allopurinol HLA allele

Answer 31

HLA-B*58:01 | Increased risk of SJS/TEN and DRESS - drug related eosinophillia.

Question 32

Carbamazepine/oxcarbazepine HLA allele(s)

Answer 32

HLA-B*15:02 --> greater risk of SJS and TEN HLA-A*31:01 --> greater risk of MPE, DRESS, SJS/TEN

Question 33

What is the implication of the VKORC1 variant?

Answer 33

WT G allele is replaced by A allele. Leads to less VKORC1 made. These patients need lower doses of warfarin.

Question 34

What is the implication of medium activity OAT1B1?

Answer 34

TC genotype Have intermediate myopathy risk Recommendation: use low dose or alt

Question 35

Carbamazepine/oxcarbazepine recommendation

Answer 35

Screen for both alleles in naive patients. Avoid use and use alt if positive for either.

Question 36

What is the implication of reduced function OAT1B1?

Answer 36

CC genotype Carriers have high myopathy risk Recommendation: use low dose or alt & consider routine CK monitoring

Question 37

What is the risk of slow acetylators of NAT2 and isoniazid and sulfonamides?

Answer 37

Isoniazid: increased hepatotoxicity (more toxic metabolite) Sulfonamides: hypersensitivity reactions

Question 38

What are the CPIC guidelines for ami/nortriptyline dosing?

Answer 38

UM/PM: avoid, use alt. | IM: Consider reducing dose 25% to start

Question 39

What are the CPIC guidelines for paroxetine dosing?

Answer 39

UM: consider alternative EM/IM: No change PM: consider alt. or reduce dose 50%

Question 40

What are the CPIC guidelines for codeine dosing?

Answer 40

UM/PM: avoid, use alt (but for different reasons) UM: risk of toxicity PM: lack of efficacy IM: use normal dose or use alt.

Question 41

What are the CPIC guidelines for phenytoin dosing?

Answer 41

``` 2D6: IM *2: drop starting dose 25% PM *3: drop starting dose 50% titrate with TDM for both HLA-B*15:02: If phenytoin naive do not use ```