IC 4 (Pgx) Flashcards
Factors that contribute to response to medications
- Patient genotype (unknown) 20-95%
- Weight
- Gender
- Ethnicity
- Diet
- Compliance
- Concomitant disease
- Concomitant drugs
- Age
91-99% of patients/ pop carry ___ pgx variant
≥1 clinically actionable PGx variant
____ of pts have been prescribed a drug for which they are predicted to have an atypical response
~24% prescribed with drugs that are potentially affected by pgx interactions
Pgx pharmacist role
promote safe, effective, cost-efficient medication use
how pgx affects PD-PK
PK changes
a. Enzyme activity
b. CYP2C19
PD changes
a. Receptor activity
b. SLC6A4
Effect: increased toxicity/ decr efficacy etc
SNP definition
single nucleotide polymorphism/ single base pair substitution
eg of structural variation
insert/ delete/ inversion/ copy number of variation (duplicate)
allele
same =
diff =
version of a gene (2 allele - mother, father)
- Same allele inherited: HOMOZYGOUS
- Diff allele inherited: HETEROZYGOUS
haplotype
set of DNA variations inherited together on the same allele
(on same strand of the DNA)
genotype vs phenotype
- Genotype: combination of alleles at a SPECIFIC location in DNA
- Phenotype: OBSERVABLE TRAITS based on genotype
(URM, RM, NM, IM, PM)
(LoF, GoF)
phenotype affected by other clinical factors
- Organ function
- Drug interaction
- See impact based on activity score
interpret pgx by:
1) FOCUS on phenotype
2) FIGURE out implications on drug therapy
3) FULL picture, then prescribe
- Eg drug allergy?
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)
- 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)
wild type allele means __
absence of variants included in the test
likely most popular variant
genotyping is to __
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)
sequencing is to __
identify ALLL variants within region tested
ADV: identify rare variants
disadv: expensive, longer time, limited clinical infor to identify effect of variant
phenoconversion definition
&
3 factors that affect it
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
statins reduce dose when
ABCG2 c.421(rosu - poor)
CYP2C9 (fluva - poor)
!!! SLCO1B1 (atorva, rosu, fluva - poor)
PPI
CYP2C19 1717 - ultrarapid metaboliser (incr dose by 100%)
CYP2C19 - poor metaboliser (reduce 50% for daily dose, same starting)
CLopidogrel
CYP2C19 - poor metaboliser (Avoid clopidogrel if possible. Use prasugrel or ticagrelor)
URM - no action
TCA
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)
SSRI
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)
tramadol, opioids
CYP2D6 URM – avoid codeine, tramadol (toxicity)
PM– avoid due to lack of efficacy choose non-opioid/ tramadol analgesia
hydrocodone has no recommendation
warfarin
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
carbamazepine
oxCBP
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
abacavir
HLA-B*57:01 positive / carrier: Significantly increased risk of abacavir hypersensitivity (not recommended)
allopurinol
HLA-B*58:01 positive: Significantly increased risk of allopurinol-induced SCAR – allopurinol CI
inhibitors/ inducers of CYP2C19
Inhibitors:
* Fluconazole
Moderate
○ Clarithromycin
○ Fluoxetine
○ fluvoxamine
○ Ketoconazole
○ Omeprazole
Inducers:
* Carbamazepine
* Phenytoin
* Rifampicin
CYP2C9 inhibitors/ inducers
Inhibitors:
* Fluconazole
Moderate
□ Amiodarone
□ Ketoconazole
□ Ritonavir
□ Voriconazole
Inducers:
* Phenobarbital
* Phenytoin
* Rifampicin
CYP2D6 inhibitors
strong: Fluoxetine, sertraline
Paroxetine, Duloxetine, Bupropion, Quinidine, ritonavir, terbinafine.
prodrugs
Tramadol CYP2D6 –> O-desmethyl-tramadol
Codeine CYP2D6 –> morphine
Tamoxifen CYP2D6 –> endoxifen
Losartan, candesartan (1st pass metabolism) CYP2C9
Clopidogrel CYP2C19
PPV for allopurinol, abacavir, CBP
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
