IC 4 (Pgx)

Question 1

Factors that contribute to response to medications

Answer 1

• Patient genotype (unknown) 20-95%
• Weight
• Gender
• Ethnicity
• Diet
• Compliance
• Concomitant disease
• Concomitant drugs
• Age

Question 2

91-99% of patients/ pop carry ___ pgx variant

Answer 2

≥1 clinically actionable PGx variant

Question 3

____ of pts have been prescribed a drug for which they are predicted to have an atypical response

Answer 3

~24% prescribed with drugs that are potentially affected by pgx interactions

Question 4

Pgx pharmacist role

Answer 4

promote safe, effective, cost-efficient medication use

Question 5

how pgx affects PD-PK

Answer 5

PK changes
a. Enzyme activity
b. CYP2C19

PD changes
a. Receptor activity
b. SLC6A4

Effect: increased toxicity/ decr efficacy etc

Question 6

SNP definition

Answer 6

single nucleotide polymorphism/ single base pair substitution

Question 7

eg of structural variation

Answer 7

insert/ delete/ inversion/ copy number of variation (duplicate)

Question 8

allele

same =
diff =

Answer 8

version of a gene (2 allele - mother, father)

• Same allele inherited: HOMOZYGOUS
• Diff allele inherited: HETEROZYGOUS

Question 9

haplotype

Answer 9

set of DNA variations inherited together on the same allele

(on same strand of the DNA)

Question 10

genotype vs phenotype

Answer 10

• Genotype: combination of alleles at a SPECIFIC location in DNA
• Phenotype: OBSERVABLE TRAITS based on genotype

(URM, RM, NM, IM, PM)
(LoF, GoF)

Question 11

phenotype affected by other clinical factors

Answer 11

• Organ function
• Drug interaction
• See impact based on activity score

Question 12

interpret pgx by:

Answer 12

1) FOCUS on phenotype
2) FIGURE out implications on drug therapy
3) FULL picture, then prescribe
- Eg drug allergy?

Question 13

4 pgx resources

• pharmVar
  ○ (look at particular variant if it has been reported before, usually for sequencing - see if yellow star is pathogenic variant or not)

Answer 13

• CPIC (US) - guidelines https://cpicpgx.org/
• DPWG (dutch)
• PharmGKB (one stop database 3*)
  ○ Prescribing info
  ○ Drug label annotations
• Sequence2script.com https://sequence2script.com/#/
  ○ Generate report that presents known recommendations for meds that could be affected by a pt’s genotype
  ○ Phenotype adjusted for concomitant medications (phenoconversion)

Question 14

wild type allele means __

Answer 14

absence of variants included in the test

likely most popular variant

Question 15

genotyping is to __

Answer 15

tests for SPECIFIC variants

adv: less expensive, less turn around time, variants based on pop freq

disadv: Will miss out variants not included in test (that could affect enzyme/ protein)

Question 16

sequencing is to __

Answer 16

identify ALLL variants within region tested

ADV: identify rare variants

disadv: expensive, longer time, limited clinical infor to identify effect of variant

Question 17

phenoconversion definition

&

3 factors that affect it

Answer 17

Phenotype may be altered by environmental factors:

□ Additional of CYP inhibitor/ inducer

      * Sequence2script: drug-drug gene interaction based on extrapolation. take into account DOSE & DURATION OF EXPOSURE for clinical decision 
      * NM pheno + strong CYP2D6i = PM

□ Liver impairment, renal imparment
□ Nutrition

Question 18

statins reduce dose when

Answer 18

ABCG2 c.421(rosu - poor)
CYP2C9 (fluva - poor)

!!! SLCO1B1 (atorva, rosu, fluva - poor)

Question 19

PPI

Answer 19

CYP2C19 1717 - ultrarapid metaboliser (incr dose by 100%)

CYP2C19 - poor metaboliser (reduce 50% for daily dose, same starting)

Question 20

CLopidogrel

Answer 20

CYP2C19 - poor metaboliser (Avoid clopidogrel if possible. Use prasugrel or ticagrelor)

URM - no action

Question 21

TCA

Answer 21

CYP2C19 – URM and RM (more 2* amines = SE)
CYP2C19 – PM (less response, AVOID)

TCA: consider nortriptyline and desipramine dont need metabolism

CYP2D6 – URM (less effective, Alternative/ incr dose)
CYP2D6 – PM (SE, Alternative/ decr dose, AVOID AMITRPTYLINE major sub)

Question 22

SSRI

Answer 22

CYP2D6 URM (major substrates are Paroxetine, vortioxetine
CYP2D6 PM (major sub venlafaxine –> active sub)

• bypass CYP2D6: desvenlafaxine
• less specific to CYP2D6: fluoxetine

CYP2C19 URM, PM (citalopram, escita, sertraline)

CYP2B6 URM, PM (sertraline)

Question 23

tramadol, opioids

Answer 23

CYP2D6 URM – avoid codeine, tramadol (toxicity)

PM– avoid due to lack of efficacy choose non-opioid/ tramadol analgesia

hydrocodone has no recommendation

Question 24

warfarin

Answer 24

CYP2C9 – PM (risk of bleed, reduce warfarin dose)

VKORC1 encodes the vitamin K epoxide reductase protein (convert vit K epoxide –> vit K. thins), the target enzyme of warfarin.

GG/AG – lower dose than GG, due to warfarin sensitivity

Question 25

carbamazepine oxCBP

Answer 25

HLA-B*15:02 positive -- Greater risk of carbamazepine-induced SJS/TEN avoid other aromatic anticonvulsants E.g., phenytoin, phenobarbital, lamotrigine, oxcarbazepine Other gene HLA-A*31:01 (also increases hypersensitivity reaction to CBZ) * Not mandated to test in SG * More prevalent in European and Japanese populations , A/w less severe reaction than SJS/TENs * If only HLA A +ve, HLAB -ve: no recommendation as of yet to avoid other aromatic anticonvulsants

Question 26

abacavir

Answer 26

HLA-B*57:01 positive / carrier: Significantly increased risk of abacavir hypersensitivity (not recommended)

Question 27

allopurinol

Answer 27

HLA-B*58:01 positive: Significantly increased risk of allopurinol-induced SCAR -- allopurinol CI

Question 28

inhibitors/ inducers of CYP2C19

Answer 28

Inhibitors: * Fluconazole Moderate ○ Clarithromycin ○ Fluoxetine ○ fluvoxamine ○ Ketoconazole ○ Omeprazole Inducers: * Carbamazepine * Phenytoin * Rifampicin

Question 29

CYP2C9 inhibitors/ inducers

Answer 29

Inhibitors: * Fluconazole Moderate □ Amiodarone □ Ketoconazole □ Ritonavir □ Voriconazole Inducers: * Phenobarbital * Phenytoin * Rifampicin

Question 30

CYP2D6 inhibitors

Answer 30

strong: Fluoxetine, sertraline Paroxetine, Duloxetine, Bupropion, Quinidine, ritonavir, terbinafine.

Question 31

prodrugs

Answer 31

Tramadol CYP2D6 --> O-desmethyl-tramadol Codeine CYP2D6 --> morphine Tamoxifen CYP2D6 --> endoxifen Losartan, candesartan (1st pass metabolism) CYP2C9 Clopidogrel CYP2C19

Question 32

PPV for allopurinol, abacavir, CBP

Answer 32

Allopurinol: General pop PPV at 2% HLAB5801 Allopurinol in renal impairment population PPV went up to 18% abacavir: PVP about 50% HLAB5701 CBP PPV is 42% for asian HLAB1502