Week 2: Application of Pharmacogenomics (cardiology drugs)

Differential Drug Response

same symptoms/ same findings/ same disease ←→ different patients ←→ same drug/ same dose ←→ different effects

at recommended prescribed dosage:

a drug is _________ in most (eventually)

it is ________ in some others

it is ________ in a few patients

effective, ineffective, harmful

Genetic Variation

~10-20 million ________ in each person’s genome, most of which have no discernable effect

SNPs (single nucleotide polymorphisms)

Genetic Variation

~10-20 million SNPs in each person’s genome, most of which have _______ effect

no

Genetic Variation

~10-20 million SNPs in each person’s genome, most of which have no discernable effect

SNPs occurring within ______-coding regions can cause alterations in ______ structure and/or function; causes observable differences in phenotype

protein (and promotor region)

Genetic Variation

True or False: SNPs occurring within the protein-coding region often have no discernable effects

False (they often have observable differences in phenotype)

Genetic Variation

~10-20 million SNPs in each person’s genome, most of which have no discernable effect

SNPs in _________ regions CAN (not will) affect phenotype by multiple mechanisms

non-coding

Genetic Variation

True or False: SNPs in non-coding regions can affect phenotype by multiple mechanisms

True (it does not mean they always will, they jut have the ability to)

Pharmacogenomics and Metabolism

Lipophilic drug → drug metabolism → ________ ________ __________ → excretion (urine, bile)

water soluble metabolite

Pharmacogenomics and Metabolism

Lipophilic drug → drug metabolism → water soluble metabolite → excretion (urine, bile)

drug metabolism is phase I: chemical reactivity, __________ reduction, __________, and _______

oxidation, hydrolysis, CYP450s

Pharmacogenomics and Metabolism

Lipophilic drug → drug metabolism → water soluble metabolite → excretion (urine, bile)

water soluble metabolites are made via phase II: conjugation with polar group, ____________, sulphation, glutathione conjugation, and transferases

glucuronidation

True or False: TPMT is a Phase II enzyme

True (ex: thiopurines)

True or False: CYP2C9, CYP2C19, CYP2D6, and others are Phase II enzymes

False (CYP450s are phase I)

True or False: CYP2C9, CYP2C19, CYP2D6, and others are Phase I enzymes

True

Clopidogrel: antiplatelet that inhibits P2Y₁₂ class of adenosine diphosphate receptor → inhibits platelet aggregation

is this a prodrug: yes or no

yes (metabolized into active metabolite by CYP3A4 and CYP2C19)

Clopidogrel: antiplatelet that inhibits P2Y₁₂ class of adenosine diphosphate receptor → inhibits platelet aggregation

it is a prodrug that gets metabolized into active metabolite via _________(mostly) and ________

CYP2C19, CYP3A4

____________: antiplatelet that inhibits P2Y₁₂ class of adenosine diphosphate receptor → inhibits platelet aggregation

it is a prodrug that gets metabolized into active metabolite via CYP2C19 (mostly) and CYP3A4

Clopidogrel

Clopidogrel: antiplatelet that inhibits P2Y₁₂ class of adenosine diphosphate receptor → inhibits platelet aggregation (it is a prodrug)

FDA BBW: ________ metabolizers have higher CV event rates following acute coronary syndrome or PCI than patients with normal CYP2C19 function

poor

Clopidogrel: antiplatelet that inhibits P2Y₁₂ class of adenosine diphosphate receptor → inhibits platelet aggregation (it is a prodrug)

___________ (efficacy or toxicity) of Clopidogrel depends on activation mainly by CYP2C19

efficacy

Clopidogrel: antiplatelet that inhibits P2Y₁₂ class of adenosine diphosphate receptor → inhibits platelet aggregation (it is a prodrug)

FDA BBW: poor metabolizers have higher CV event rates following acute coronary syndrome or PCI than patients with normal CYP2C19 function

alternative options for poor-CYP2C19 metabolizers are ________ or ________

Prasugrel or Ticagrelor (Pras uses 3A4 and 2B6🙂Tica is not a prodrug and uses 3A4/5🙂)

Warfarin indicated for Afib, VTE treatment and prohy

MOA: inhibits vitamin K epoxide reductase (VKORC1) enzyme complex

mainly metabolized by _________

AEs: bleeding, tissue necrosis, hypersensitivity

CYP2C9

__________ indicated for Afib, VTE treatment and prohy

MOA: inhibits vitamin K epoxide reductase (VKORC1) enzyme complex

mainly metabolized by CYP2C9

AEs: bleeding, tissue necrosis, hypersensitivity

warfarin

Warfarin: inhibits vitamin K epoxide reductase (VKORC1) enzyme complex

Pharmacodynamic targets: common variant is upstream of the VKORC1 gene (i.e. in the ________ region)

promotor

Warfarin: inhibits vitamin K epoxide reductase (VKORC1) enzyme complex

Pharmacodynamic targets: common variant is upstream of the VKORC1 gene

decreased conversion of vitamin-K epoxide into vitK

“warfarin ________”

sensitivity

Warfarin: inhibits vitamin K epoxide reductase (VKORC1) enzyme complex

VKORC1 *2 allele: Guanine

functional status is ________

normal (reduced warfarin sensitivity → no dose change required)

Warfarin: inhibits vitamin K epoxide reductase (VKORC1) enzyme complex

VKORC1 *2 allele: Guanine

functional status is normal → phenotype is ________ warfarin sensitivity

reduced

Warfarin: inhibits vitamin K epoxide reductase (VKORC1) enzyme complex

VKORC1 *2 allele: Guanine

functional status is normal → phenotype is reduced warfarin sensitivity → change in warfarin dose?

no

Warfarin: inhibits vitamin K epoxide reductase (VKORC1) enzyme complex

VKORC1 *2 allele: Adenine

functional status is _________

decreased

Warfarin: inhibits vitamin K epoxide reductase (VKORC1) enzyme complex

VKORC1 *2 allele: Adenine

functional status is decreased → phenotype is _________ warfarin sensitivity

increased

Warfarin: inhibits vitamin K epoxide reductase (VKORC1) enzyme complex

VKORC1 *2 allele: Adenine

functional status is decreased → phenotype is increased warfarin sensitivity → change in warfarin dose?

decrease 2-3 mg/day

CPIC Recommendations: Warfarin

_________ is a major decision point → determines if PGx-guided dosing is appropriate (depending on CYP2C9 variants tested)

ancestry

Warfarin: inhibits vitamin K epoxide reductase (VKORC1) enzyme complex

VKORC1 *2 allele: Adenine or Guanine

Warfarin PGx Dosing can be done via a _______ dosing _______ (added to FDA drug label in 2007) or online via a dosing _________ (more accurate approach)

fixed dosing table, algorithm

__________: VKORC1 *2 allele: Adenine or Guanine

__________ PGx Dosing can be done via a fixed dosing table (added to FDA drug label in 2007) or online via a dosing algorithm (more accurate approach)

warfarin

Statins: HMG-CoA reductase inhibitors used in hyperlipidemia and prevention of CAD

most common AE is ________ ________ (prevalence 1-5%)

muscle toxicity

Statins: HMG-CoA reductase inhibitors used in hyperlipidemia and prevention of CAD

SLCO-1B1 encodes the drug transporter ______ which facilitates hepatic uptake of statins

OATP1B1

Statins: HMG-CoA reductase inhibitors used in hyperlipidemia and prevention of CAD

_________ encodes the drug transporter OATP-1B1 which facilitates hepatic uptake of statins

SLCO-1B1

SLCO-1B1 encodes the drug transporter OATP-1B1 which facilitates hepatic uptake of _________ (med class)

statins

Statins: HMG-CoA reductase inhibitors used in hyperlipidemia and prevention of CAD

SLCO-1B1 encodes the drug transporter OATP-1B1 which facilitates hepatic uptake of statins

PD impact: decreased transporter function → ________ risk of statin-induced myopathy

increased

Statins: HMG-CoA reductase inhibitors used in hyperlipidemia and prevention of CAD

SLCO1B1 encodes drug transporter OATP1B1 which facilitates hepatic uptake of statins for metabolism

increased function: what should we do for the starting dose?

any starting dose (for all statins)

Statins: HMG-CoA reductase inhibitors used in hyperlipidemia and prevention of CAD

SLCO1B1 encodes drug transporter OATP1B1 which facilitates hepatic uptake of statins for metabolism

normal function: what should we do for the starting dose?

any starting dose (for all statins)

Statins: HMG-CoA reductase inhibitors used in hyperlipidemia and prevention of CAD

SLCO1B1 encodes drug transporter OATP1B1 which facilitates hepatic uptake of statins for metabolism

decreased function: what should we do for the starting dose?

lower it (but not as low as you would for poor fxn)

Statins: HMG-CoA reductase inhibitors used in hyperlipidemia and prevention of CAD

SLCO1B1 encodes drug transporter OATP1B1 which facilitates hepatic uptake of statins for metabolism

poor function: what should we do for the starting dose?

lower it (even lower than for decreased fxn)

Statins: HMG-CoA reductase inhibitors used in hyperlipidemia and prevention of CAD

SLCO1B1 encodes drug transporter OATP1B1 which facilitates hepatic uptake of statins for metabolism

decreased function: __________ and _________ should be switched to alternate statins, the dose would have to be so low that the statin would not be effective

Lovastatin, Simvastatin

Rosuvastatin: HMG-CoA reductase inhibitor used in hyperlipidemia and prevention of CAD

ABCG2 encodes the transporter BCPR which facilitates export of compounds from the cell

the A allele is associated with __________ expression of the transporter → __________ exposure to Rosuvastatin

decreased, increased

Rosuvastatin: HMG-CoA reductase inhibitor used in hyperlipidemia and prevention of CAD

ABCG2 encodes the transporter BCPR which facilitates export of compounds from the cell

ABCG2 normal and decreased function: what should we do for the starting dose?

any starting dose (unless pt is also a SLCO1B1 poor function then we need to decrease obvi)

Rosuvastatin: HMG-CoA reductase inhibitor used in hyperlipidemia and prevention of CAD

ABCG2 encodes the transporter BCPR which facilitates export of compounds from the cell

ABCG2 poor function: what should we do for the starting dose?

lower dose (and even lower if pt is also a SLCO1B1 poor function)

_____________ (which statin): HMG-CoA reductase inhibitor used in hyperlipidemia and prevention of CAD

ABCG2 encodes the transporter BCPR which facilitates export of compounds from the cell

Rosuvastatin

Fluvastatin: HMG-CoA reductase inhibitor used in hyperlipidemia and prevention of CAD

metabolized by CYP2C9 → reduced function → __________ Fluvastatin exposure

increased

____________ (which statin): HMG-CoA reductase inhibitor used in hyperlipidemia and prevention of CAD

metabolized by CYP2C9 → reduced function → increased statin exposure

Fluvastatin

Fluvastatin: HMG-CoA reductase inhibitor used in hyperlipidemia and prevention of CAD

metabolized by CYP2C9; in patients who are intermediate or poor metabolizers, what should we do for the starting dose?

decrease it (if pt is also SLCO1B1 poor function, probably use an alternative statin)

If you have test results stating your genotype is CYP2C9 *2/*3 and VKORC1 AA, what approximate warfarin dose range should you likely expect to start at?

a. lower than average dose

b. average dose

c. higher than average dose

a

genotype CYP2C9 is *2/*3; what Clopidogrel dose should you start at?

a. normal metabolizer; standard dose

b. intermediate metabolizer; standard dose

c. poor metabolizer; alternative dose

c

if you are a patient taking Simvastatin and have test results stating that your SLCO1B1 genotype is CC, which of the following is true?

a. high risk to develop myopathy, use alternative therapy

b. intermediate risk to develop myopathy, use lower dose

c. low risk to develop myopathy, use normal dose

a