Pharmacogenomics (PGx)

Question 1

Substrates (5) and inhibitors (1) of:
Sertaline

Answer 1

Substrates: CYP3A4 (major), CYP2B6 (minor), CYP2C19 (minor), CYP2D6 (minor), CYP2C9 (minor)

Inhibitor: CYP2D6 (weak)

Question 2

Abacavir

anti-HIV

Answer 2

HLA-B*5701

HLA-B5701 (-): Use abacavir per standard dosing guidelines
HLA-B5701 (+): Abacavir is not recommended

Question 3

Substrates and inhibitors of:
Hydrocodone

Answer 3

Substrates: CYP2D6 (minor, active > Hydromorphone) CYP3A4 (major)

Question 4

Tramadol

Pain

Answer 4

CYP2D6

URM (AS > 2.25): Avoid tramadol. Consider non-codeine opioid

NM/IM (0 < AS < 2.25): Use tramadol as per normal

PM (AS = 0): Avoid tramadol use because of diminished analgesia

Question 5

Substrates (7) and inhibitors (2) of:
Fluoxetine

Answer 5

Substrates: CYP1A2 (minor), CYP2B6 (minor), CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP2E1 (minor), CYP3A4 (minor)

Inhibitor: CYP2D6 (strong), CYP2C19 (moderate)

Question 6

Substrates (2) and inhibitors (0) of:
Oxycodone

Answer 6

Substrates: CYP2D6 (minor), CYP3A4 (major)

Question 7

Substrates (2) and inducers (8) of:
Carbamazepine

Answer 7

Substrates: CYP2C8 (minor), CYP3A4 (major)

Inducer: BCRP/ABCG2, CYP1A2 (weak), CYP2B6 (moderate), CYP2C9 (weak), CYP3A4 (strong), SLCO1B1/1B3, P-glycoprotein, UGT1A1

Question 8

Statins

Hyperlipidemia

Answer 8

SLCO1B1

↑ /Normal func: Prescribe desired starting dose

↓ func: Prescribe ≤40mg (starting dose)

Poor func: Prescribe ≤20mg (starting dose)

Question 9

Vortioxetine

SSRI

Answer 9

CYP2D6

URM: Select alternative antidepressant, else initiate at standard dose and consider increasing maintenance dose by 50%

NM/IM: Initiate therapy at recommended starting dose

PM: Initiate 50% of starting dose, else consider alternative antidepressant

Question 10

Substrates (7) and inhibitors (1) of:
Bupropion

Answer 10

Substrates: CYP2B6 (major), CYP1A2 (minor), CYP2A6 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP2E1 (minor), CYP3A4 (minor)

Inhibitor: CYP2D6 (strong)

Question 11

Sertraline

SSRI

Answer 11

CYP2C19

UM/RM/NM: Initiate therapy with recommended starting dose

IM: Initiate with recommended starting dose, but consider a slower titration schedule and lower maintenance dose

PM: Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose

CYP2B6

UM/RM/NM: Initiate therapy with recommended starting dose

IM: Initiate therapy with recommended starting dose, but lower maintenance dose and slowly titrate.

PM: Consider a lower starting dose, slower titration schedule and 25% of standard maintenance dose

Question 12

Substrates (3) and inducers (6) of:
Phenytoin

Answer 12

Substrates: CYP2C19 (major), CYP2C9 (major), CYP3A4 (minor)

Inducer: CYP1A2 (weak), CYP2B6 (weak), CYP3A4 (strong), P-GP/ABCB1, UGT1A1, UGT1A4

Question 13

Paroxetine

SSRI

Answer 13

CYP2D6

UM (AS > 2.25): Select alternative drug not predominantly metabolized by CYP2D6.

NM (1.25<AS<2.25): Initiate therapy with recommended starting dose.

IM (0<AS<1.25): Consider a lower starting dose and slower titration schedule as compared to normal metabolizer

PM: Select an alternative drug not predominantly metabolized by CYP2D6/ If paroxetine use is warranted, consider a 50% reduction in recommended starting dose, slower titration schedule, and a 50% lower maintenance dose as compared to normal metabolizers.

Question 14

Phenytoin

Antipsychosis

Answer 14

HLA-B *15:02

HLA-B15:02 (-): Use at standard dosings.
HLA-B15:02 (+): If the patient is phenytoin-naive, do not use phenytoin/fosphenytoin. Also avoid carbamazepine/ oxcarbamazepine.

If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future.

CYP2C9

Norm. (AS 2)/ Inter. (AS 1.5) Metab.: No adjustments needed from typical dosing strategies.

Inter. Metab. (AS 1): For first dose, use typical initial or loading dose. For subsequent doses, use approximately 25% less than typical maintenance dose.

Poor Metab.: For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose.

Question 15

Substrates (4) and inhibitors (0) of:
Venlafaxine

Answer 15

Substrates: CYP3A4 (minor), CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (minor > Active metabolite [Desvenlafaxine])

Question 16

Substrates (4) and inhibitors (0) of:
Nortriptyline

Answer 16

Substrate: CYP1A2 (minor), CYP2C19 (minor), CYP2D6 (major), CYP3A4 (minor)

Question 17

Substrates (3) and inhibitors (1) of:
Escitalopram/ citalopram

Answer 17

Substrates: CYP2C19 (major), CYP2D6 (minor), CYP3A4 (minor)

Inhibitor: CYP2D6 (weak)

Question 18

Substrates (4) and inhibitors (0) of:
Rosuvastatin

Answer 18

Substrates: BCRP/ABCG2, CYP2C9 (minor), CYP3A4 (minor), OATP1B1/1B3 (SLCO1B1/1B3)

Question 19

Substrates (4) and inhibitors (0) of:
Codeine

Answer 19

Substrates: CYP2D6 (major, active > Morphine), UGT2B7 and UGT2B4, CYP3A4 (major)

Question 20

Substrates (1) and inhibitors (1) of:
Abacavir

Answer 20

Substrate: BCRP/ABCG2

Inhibitor: MRP2

Question 21

Clopidogrel

Cardiovascular

Answer 21

CYP2C19

URM/RM/NM: Use at standard dose (75 mg/day)

IM/PM: Avoid standard dose clopidogrel (75 mg) if possible. Use prasugrel or ticagrelor at standard dose if no contraindication.

Question 22

Substrates (5) and inhibitors (2) of:
Omeprazole

Answer 22

Substrates: CYP2C19 (major), CYP2A6 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP3A4 (minor)

Inhibitors: CYP2C19 (weak), OAT1/3

Question 23

Clopidogrel

Neurovascular

Answer 23

CYP2C19

URM/RM: No recommendation

NM: If considering clopidogrel, use at standard dose (75 mg/day)

IM: Consider an alternative P2Y12 inhibitor at standard dose if clinically indicated and no contraindication.

PM: Avoid clopidogrel if possible. Consider an alternative P2Y12 inhibitor at standard dose if clinically indicated and no contraindication.

Question 24

Escitalopram / Citalopram

SSRI

Answer 24

Generally: Consider alternatives not predominantly metabolized by CYP2C19.

URM: If adequate efficacy is not achieved at standard maintenance dosing, consider titrating to a higher maintenance dose.

RM: Initiate therapy with recommended starting dose. If inadequate response, consider titrating to a higher maintenance dose.

NM: Initiate therapy with recommended starting dose.

IM: Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than normal metabolizers.

PM: Consider a lower starting dose, slower titration schedule and 50% reduction of the standard maintenance dose as compared to normal metabolizers.

Question 25

Substrates (3) and inhibitors (0) of: Morphine

Answer 25

Substrates: OCT, P-GP/ABCB1 (major), UGT1A

Question 26

Codeine | Cough

Answer 26

**CYP2D6** [DWG] UR: If presenting with CYP3A4 inhibitors, and/or reduced eGFR: Dose Codeine less than 20 mg q6h for adults or 10 mg q6h for children. Else, dose normally. [DWG] IM/PM: No action is required

Question 27

Oxycodone | Pain

Answer 27

CYP2D6 COMT, OPRM1 No recommedations

Question 28

Substrates (2) and inhibitors (1) of: Duloxetine

Answer 28

Substrate: CYP1A2 (major), CYP2D6 (major) Inhibitor: CYP2D6 (mod.)

Question 29

Substrates (2) and inhibitors (3) of: Clopidogrel

Answer 29

Substrates: CYP2C19 (major, **active**), CYP3A4 (minor, **active**) Inhibitors: BCRP/ABCG2, CYP2B6 (weak), CYP2C8 (moderate)

Question 30

Omeprazole | PPI

Answer 30

**CYP2C19** URM: Increase starting daily dose by 100% (given in divided doses) RM/NM: Initiate standard starting daily dose (given in divided doses). Consider increasing the dose by 50-100%. IM/PM: Initiate standard starting daily dose. For chronic therapy (>12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.

Question 31

Substrates (3) and inhibitors (0) of: Tramadol

Answer 31

Substrates: CYP2B6 (minor), CYP2D6 (major, **active**), CYP3A4 (major, **inactive**)

Question 32

What is phenoconversion?

Answer 32

Phenotype clinically deviates from the genotype, and can be due to many factors such as drug interactions, organ functions and nutrition.

Question 33

Codeine | Pain

Answer 33

**CYP2D6** UM (AS > 2.25): Avoid use of codeine due to toxicity. If opioid use is warranted, consider a non-tramadol opioid. NM/IM (0 < AS < 2.25): Use codeine as per label PM (AS = 0): Avoid codeine due to possible diminished analgesia

Question 34

Substrates (2) and inhibitors (1) of: Paroxetine

Answer 34

Substrates: CYP2D6 (major), CYP3A4 (major) Inhibitor: ABCB1

Question 35

Fluvoxamine | SSRI

Answer 35

**CYP2D6** UM: No recommendation due to lack of evidence NM/IM: Recommended starting dose PM: Consider a 25–50% lower starting dose and slower titration schedule or consider an alternative antidepressant not predominantly metabolized by CYP2D6

Question 36

Substrates (4) and inhibitors (0) of: Mirtazapine

Answer 36

Substrate: CYP1A2 (minor), CYP2C19 (minor), CYP2D6 (minor), CYP3A4 (major)

Question 37

Substrates (4) and inhibitors (0) of: Other Statins

Answer 37

Substrates: BCRP/ABCG2, CYP3A4 (major), SLCO1B1, P-glycoprotein (minor)

Question 38

Amitriptyline / Nortriptyline / Desipramine / Clomipramine | TCA

Answer 38

**CYP2D6** (Amitriptyline/Nortriptyline/Desipramine/Clomipramine) URM: Avoid TCA due to potential lack of efficacy. Consider alternative drug not metabolised by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose. NM: Initiate therapy with recommended starting dose. IM: Consider a 25% reduction of recommended starting dose. PM: Avoid TCA use due to potential for side effects. Consider alternative drug not metabolised by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose. **CYP2C19** (Amitriptyline/Clomipramine) URM/RM: Consider alternative drug not metabolised by CYP2C19. TCAs without major CYP2C19 include nortriptyline and desipramine. NM/IM: Initiate therapy with recommended starting dose. PM: Consider alternative drug not metabolised by CYP2C19. TCAs without major CYP2C19 include nortriptyline and desipramine. For tertiary amines, consider 50% reduction of recommended starting dose

Question 39

Carbamazepine | Anti-epileptic

Answer 39

**HLA-B*15:02** HLA-B*15:02 (-): Use carbamazepine per standard dosing guidelines HLA-B*15:02 (+): If patient is carbamazepine-naive, do not use carbamazepine. If the patient has previously used carbamazepine consistently for longer than 3 months without incidence of cutaneous adverse reactions, cautiously consider use of carbamazepine in the future. **HLA-A*31:01** HLA-A*31:01 (-): Use carbamazepine per standard dosing guidelines HLA-A*31:01 (+): If patient is carbamazepine-naive and alternative agents are available, do not use carbamazepine. If patient is carbamazepine-naive and alternative agents are not available, consider the use of carbamazepine with increased frequency of clinical monitoring. Discontinue therapy at first evidence of a cutaneous adverse reaction. If patient has previously used carbamazepine for > 3 months without incidence of cutaneous adverse reactions, cautiously consider use of carbamazepine.

Question 40

Substrates (6) and inhibitors (0) of: Amitriptyline

Answer 40

Substrate: CYP1A2 (minor), CYP2B6 (minor), CYP2C19 (minor), CYP2C9 (minor), CYP3A4 (minor), CYP2D6 (major > Nortriptyline [active])

Question 41

Substrates (2) and inhibitors (5) of: Fluvoxamine

Answer 41

Substrates: CYP1A2 (minor), CYP2D6 (minor) Inhibitor: CYP1A2 (strong), CYP2C19 (mod.), CYP2C9 (weak), CYP2D6 (weak), CYP3A4 (weak)

Question 42

Allopurinol | Gout

Answer 42

**HLA-B *58:01** HLA-B*58:01 (-): Use allopurinol per standard dosing guidelines HLA-B*58:01 (+): Allopurinol is contraindicated **ABCG2** G/G: Normal genotype. Dosing schedule of 100, 200, 300 and 400 mg/day. G/T: Use 1.25X the standard dose. Dosing schedule of 100, 200, 400 and 500 mg/day T/T: Use 1.4X the standard dose. Dosing schedule of 100, 300, 400, 600 and 700 mg/day

Question 43

Substrates (1) and inhibitors (0) of: Desvenlafaxine

Answer 43

Substrate: CYP3A4 (minor)

Question 44

Venlafaxine | SNRI

Answer 44

**CYP2D6** UM/NM/IM (0< AS< 2.25): Initiate therapy with recommended starting dose PM: Consider alternative antidepressant