PHPR-887 Exam 1

what allele of CYP2C9 increases your dose of warfarin

*1/*1

what genotype is a normal metabolizer for CYP2C19?

*1/*1

what genotype is a rapid metabolizer for CYP2C19?

*1/*17

what genotype is an intermediate metabolizer for CYP2C19?

*1/*2, *1/*3, *2/*17, *3/*17

what star alleles increase CYP2C19 activity what does this mean for clopidogrel efficacy?

*17 enhanced active metabolite, continue dose promoter (enhanced transcription)

what genotype is an ultrarapid metabolizer for CYP2C19?

*17/*17

what star alleles reduce CYP2C19 activity what does this mean for clopidogrel efficacy?

*2 and *3 poor metabolizer less efficacy

what genotype is a poor metabolizer for CYP2C19?

*2/*2, *3/*3, *2/*3

what allele of CYP2C9 decreases your dose of warfarin

*3/*3

what genotype indicated a likely poor metabolizer and likely intermediate metabolizer for CYP2C19?

*9

boxed warning for clopidogrel

- warning about reduced effetiveness in patient who are poor metabolizers of Plavix. Poor metabolizers do not effectively convert Plavix to its active form - Inform healthcare professional to consider use of another antiplatelet med or alternative dosing for Plavix in pts identified as poors metabolizers

pitavastatin max dose for SLCO1B1 poor function

1 mg

Class II MHC gene characteristics

1. mediates immune responses against exogenous antigens (antigens found outside of the cell, the cytosol) 2. class II involved in regulation of the cells of the immune systems 3. MHC class 2 will bind w peptides 13-18 AAs that will be recognized by T helper cells 4. found on B lymphocytes, macrophages

which of the following is a gain of function allele for CYP2C19 1 17 3 2

17

pitavastatin max dose for SLCO1B1 decreased function

2 mg

atorvastatin max dose for SLCO1B1 poor function

20 mg

rosuvastatin max dose for SLCO1B1 poor function

20 mg

atorvastatin max dose for SLCO1B1 decreased function

40 mg

fluvastatin max dose for SLCO1B1 poor function

40 mg

pravastatin max dose for SLCO1B1 poor function

40 mg

what allele of VKORC1 decreases your dose of warfarin

A/A

prasugrel BBW/CI and things to remember when to dose reduce?

BBW/CI: previous stroke/ TIA cannot be used not recommended for 75 and older or propensity to bleed dose reduce: body weight of 60 kg or less, then a dose reduction to 5 mg

polymorphysims of what gene will effect clopidogrel metobolism

CYP2C19

what also influences Fluvastatin polymorphisms on top of SLCO1B1 function

CYP2C9

what is the pharmacokinetic target for warfarin

CYP2C9

simvastatin is metabolized by

CYP3A4

GP has epilepsy and is starting treatment with phenytoin. His CYP2C9 genotype is *2/*2. According to CPIC guidelines, what is the clinical recommendation if GP is not a carrier of HLA-B*15:02? a) Use the normal phenytoin starting dose b) Consider a 25% reduction in phenytoin starting dose c) Consider a 50% reduction in phenytoin starting dose d) Use an alternative anti-epileptic drug

Consider a 50% reduction in phenytoin starting dose

Which one of the following statements is NOT true when considering atazanavir and its relation to UGT1A1? a. UGT1A1 genotypes could have significant cosmetic concerns for some patients if initiated on atazanavir b. Depending on the UGT1A1 alleles present, patients may be at severely increased risk of liver dysfunction from atazanavir c. Genotyping for UGT1A1 does not need to be done for everyone prior to initiating atazanavir d. Atazanavir does not necessarily need to be discontinued in a patient who experiences bilirubin increases despite having an intermediate or poorly metabolizing UGT1A1 phenotype

Depending on the UGT1A1 alleles present, patients may be at severely increased risk of liver dysfunction from atazanavir (Correct)

what allele of VKORC1 increases your dose of warfarin

GG

Which of the following HLA alleles is defined as a class II allele? (select all that apply) HLA-B*5701 HLA-A*1002 HLA-DR*0302 HLA-DQ*0101 HLA-C*3708

HLA-DR*0302 HLA-DQ*0101

should we ever choose ticlopidine on an exam?

NOOOOOOO

simvastatin is transported into the liver by

SLCO1B1 (OAT1B1)

Stevens-Johnson Syndrome induced by lamotrigine would be classified as a Type 2 adverse drug reaction. True False

True

what is the pharmacodynamic target for warfarin

VKORC1 inhibition

Match the following CYP2C19 diplotypes to phenotypes. Intermediate metabolizer Ultra-rapid (Rapid) metabolizer Extensive (Normal) metabolizer Poor metabolizer 1. *1/*17 2. *2/*3 3. *1/*2 4. *1/*1

__3__ Intermediate metabolizer __1__ Ultra-rapid (Rapid) metabolizer __4__Extensive (Normal) metabolizer __2__Poor metabolizer

Match the following drugs with the HLA allele that predict a sever adverse drug reaction carbamazepine allopurinol abacavir lamotrigine phenytoin 1. HLA-B*5701 2. HLA-B*5801 3. HLA-B*1502 4. HLA-B*3801

__3__carbamazepine __2__allopurinol __1__abacavir __4__lamotrigine __3__phenytoin

Match the following statins to their maximum doses in a patient with poor SLCO1B1 function: 1 mg_ 40 mg 20 mg 0 mg (avoid altogether) 1. atorvastatin 2. simvastatin 3. pravastatin 4. pitavastatin

__4_pitavastatin_1 mg __3_pravastatin_40 mg __1_atorvastatin_20 mg __2_simvastatin_0 mg (avoid altogether)

Which of the following genotypes for CYP2C19 would voriconazole use NOT be discouraged in? a. *2/*17 b. *17/*17 c. *2/*3 d. *3/*3

a. *2/*17

Regarding CYP2B6 516G>T, the AUC for a homozygous T patient is approximately how much greater than a homozygous G patient when both are administered the same dose of efavirenz? a. 2-3x b. 3-5x c. 5-7x d. 7-8x

a. 2-3x

Y181C is a devastating reverse transcriptase mutation that can arise in HIV-1 conferringresistance to many of the available NNRTIs. In the presence of only Y181C, whichNNRTI appears to be the least affected comparable to all other NNRTIs based on theStanford University HIV Drug Resistance Database? a. Doravirine b. Efavirenz c. Etravirine d. Nevirapine e. Rilpivirine

a. Doravirine

Genotypic testing of HIV's V3 coding region in gp120 would help elucidate what? a. Its coreceptor preference b. Its integrase resistance mutations c. If M184V is present d. All NRTI/NNRTI/PI/INSTI mutations archived within the cell

a. Its coreceptor preference

JS is a 68 yr old 59 kg female admitted to ED and diagnosed w STEMI. Prior to PCI, JS gets abciximab, aspirin 325 mg and clopidogrel 300 mg. Drug-eluting stent is placed. 4 weeks after discharge, JS readmitted and found to bave thrombosed her drug-eluting stent. Pharmacogenetic testing indicated that JS has the CYP2C19*2/*2 genotype PMH: T2D, depression, htn, and hyperlipidemia. NKDA. Takes lisinopril, aspirin, glipizide, simvastatin, sertaline, and ranitidine - What should be done to his clopidogrel regimen? a. Continued current clopidogrel dose b. increase clopidogrel dose? c. prasugrel? d. ticagrelor? e. ticlopidine?

a. JS likely clopidogrel resistant based on genotype and thrombosis b. increased clopidogrel does? not likely to help since no functional CYP2C19 c. prasugrel? body weight < 60 kg increased propensity to bleed- 5 mg daily if used d. ticagrelor? May initiate ticagrelor 90 mg BID 24 hours after last clopidogrel dose; aspirin dose should be reduced <100 mg e. ticlopidine never an option CIs and ADRs

Patient ST is a 55 year old male with a new diagnosis of hyperlipidemia today being started on a moderate intensity statin regimen. The patient has received the following genotype information from 23andme: HLA-B*5701 Negative; CYP2C9 *1/*3; CYP2C19 *1/*1; SLCO1B1 *5/*5 (rs4149056 CC); VKORC1 G/G Which of the following is a good first line option to treat ST's hyperlipidemia? a. Rosuvastatin 10 mg QHS b. Pravastatin 20 mg QHS c. Simvastatin 80 mg QHS d. Atorvastatin 40mg QHS

a. Rosuvastatin 10 mg QHS

for a person who has SLCO1B1 polymorphism of *1/*15 or *1/*5 and qualifies for high intensity statin which option has the lowest SAMS risk? a. Rosuvastatin 20 mg b. Atorvastatin 40 mg c. Rosuvastatin 40 mg d. Atorvastatin 80 mg

a. Rosuvastatin 20 mg

A patient presents with an unusual rash and shortness of breath. He reports recently having started Triumeq approximately 3 weeks ago and, 1 week later, chlorthalidone for uncontrolled blood pressure. He became worried and self-discontinued both medications approximately 5 days ago but his symptoms have failed to resolve. Select all of the following characteristics that work IN FAVOR of an abacavir-mediated hypersensitivity reaction: a. The timeframe since beginning abacavir b. The symptomatic presentation c. Lack of symptomatic improvement since discontinuing abacavir d. No other clear explanation for the symptoms

a. The timeframe since beginning abacavir b. The symptomatic presentation

for a person who has SLCO1B1 polymorphism of *1/*15 or *1/*5 and qualifies for moderate intensity statin which option has the lowest SAMS risk? a. atorvastatin 10-20 mg b. fluvastatin80 mg c. pravastatin 80 mg d. simvastatin 20-40 mg

a. atorvastatin 10-20 mg or pitavastatin 1 mg or pravastatin 40 mg or rosuvastatin 5-10 mg

for a person who has SLCO1B1 polymorphism of *1/*15 or *1/*5 and qualifies for low intensity statin which option has the lowest SAMS risk? a. fluvastatin 20-40 mg b. lovastatin 20 mg c. simvastatin 10 mg

a. fluvastatin 20-40 mg or Pravastatin 10-20 mg

Ticagrelor CI

active bleeding; hisotry of intracranial bleed

what is the SLCO1B1 *5 and *15 polymorphism associated with

associated w over 4 fold increased risk of myopathy per copy of allele (w simvastatin 80 mg)

for a person who has SLCO1B1 polymorphism of *5/*15 and qualifies for moderate intensity statin which option has the lowest SAMS risk?

atorvastatin 10-20 mg Pitavastatin 40 mg rosuvstatin 5-10 mg

for an intermediate, likely intermediate, poor, likely poor metabolizer of clopidogrel what are the clinical recommendations

avoid clopidogrel; use ticagrelor or prasugrel if no contraindications (Prasugrel contraindicated in pts w previous stroke/TIA)

for someone with a genotype of CYP2C19*1/*2, *1/*3, *2/*17, *3/*17, *2/*2, *3/*3, *2/*3 what is the CV therapeutic recommendation

avoid standard dose clopidogrel if possible. Use prasugrel or ticagrelor at standard dose if no contraindication

define class 1 MHC molecules characteristics

bind peptides derived from endogenous antigens processed in the cytoplasm 1. Peptide-binding domain: alpha1/alpha2 2. nature of peptide binding cleft: closed at both ends 3. general size of bound peptides: 8-10 amino acids 4. peptide motifs involved in binding to MHC molecule: anchor residues at both ends of peptide; generally hydrophobic carboxyl-terminal anchor 5. nature of bound peptide: extended structure in which both ends interact w MHC cleft but middle arches up away from MHC molecule

define class II MHC molecules characteristics

bind peptides derived from exogenous antigens that are internalized by phagocytosis or endocytosis and processed within the endocytic pathway alpha1/ beta 1 open at both ends 13-18 amino acids anchor residues distributed along the length of the peptide extended structure that is held at a constant elevation above the floor of the MHC cleft

JD is a 56 year old, 62 kg, 5'8'', non-Hispanic, white female being started on warfarin (INR target 2-3) for the first time (zero doses given) for a recent PE. Her baseline INR is 1.05. She does not smoke, has no history of liver disease, and takes both simvastatin and Bactrim. Here genotype results are: VKORC1 A/G, CYP2C9 *1/*2 (CYP2C9*2 and *3 tested but *5,*6,*8, and *11 not tested). According to warfarindosing.org, what is JD's estimated therapeutic daily warfarin dose (long term)? a. 6.0 mg/day b. 3.0 mg/day c. 3.3 mg/day d. 4.1 mg/day

c. 3.3 mg/day

Nevirapine skin reactions may be able to be anticipated by which HLA based on onecase-control study? a. HLA-B*57:01 b. HLA-B*20 c. HLA-Cw*04 d. HLA-DRB*01

c. HLA-Cw*04

The following are characteristics of class II MHC molecules, except: a. recognize CD4+ T cells b. are expressed by antigen presenting cells c. present peptides that are 8 - 10 amino acids d. bind peptides derived from exogenous antigens

c. present peptides that are 8 - 10 amino acids

GP has epilepsy and is starting treatment with phenytoin. His CYP2C9 genotype is *2/*2. According to CPIC guidelines, what is the clinical recommendation if GP is a carrier of HLA-B*15:02? a) Use the normal phenytoin starting dose b) Consider a 50% reduction in phenytoin starting dose c) Use an alternative anti-epileptic drug such as carbamazepine d) Use an alternative anti-epileptic drug such as valproate

d) Use an alternative anti-epileptic drug such as valproate

What tends to be the most important measure for clinical utility of genomic predictors of severe adverse drug reactions? a) specificity b) sensitivity c) positive predictive value d) negative predictive value

d) negative predictive value

G6PD A+ and G6PD A- deficiency both generally share which mutation between themselves? a. 202(G>A) b. 184G>T c. 197A>C d. 376(A>G)

d. 376(A>G)

Per CPIC guidelines, what were the approximate odds of successfully achieving SVR fora patient with HCV genotype 1 infection treated with PEG-IFN-α, RBV, and boceprevirand possessing the C/C mutation at rs12979860? a. 30% b. 60% c. 70% d. 90%

d. 90%

A patient presents to their HIV provider for a routine visit appearing jaundiced. Theyreport this as having set in shortly after starting atazanavir as part of their antiretroviralregimen. The patient is otherwise healthy. UGT1A1 genotyping is done and the patientis discovered to have a *36/*37 genotype. The doctor asks for your input on thesituation. Please select all of the following which are correct: a. The patient has Gilbert's syndrome and should not have been started onatazanavir b. The patient is an intermediate metabolizer of atazanavir and was predicted to have a 20% chance of jaundice from the medication c. The patient should be sent to the hospital for an immediate workup givenconcerns for liver failure d. A discussion should be had about the use of other possible antiretroviral agentsand the patient may switch if they like

d. A discussion should be had about the use of other possible antiretroviral agentsand the patient may switch if they like

If a patient has had pharmacogenomic testing for the CYP2C9 *2 and *3 variants only, in which of the following patients would it be inappropriate to use genotype information for warfarin dose estimation? a. Male of European descent with atrial fibrillation b. White female with a St. Jude's valve c. Female from Southeast Asia with a PE d. African American male with a DVT

d. African American male with a DVT

The same patient JD is a 56 year old, 62 kg, 5'8'', non-Hispanic, white female being started on warfarin (INR target 2-3) for the first time for a recent PE. Her baseline INR is 1.05. She does not smoke, has no history of liver disease, and takes both simvastatin and Bactrim. Here genotype results are: VKORC1 A/G, CYP2C9 *1/*2 (CYP2C9*5,*6,*8, and *11 not tested). What recommendation would you give JD if she were African American? a. 3.0 mg daily b. 3.7 mg daily for two days, then 3.0 mg daily c. 5.5 mg daily d. Disregard genotype information to estimate warfarin dose

d. Disregard genotype information to estimate warfarin dose

Which mutation did not appear to be linked to worse outcomes while on INH? a. NAT2 *7/*7 b. CYP2E1 *1A/*1A c. GSTM1 -/- d. GSTT1 -/-

d. GSTT1 -/-

Which of the following genes is not known to affect warfarin dose? a. GGCX b. NQO1 c. CYP4F2 d. SLCO1B1 e. VKORC1

d. SLCO1B1

Which of the following antiplatelet drugs is not a good first line option for a patient with the following genotype information: CYP2C9 *2/*3; CYP2C19 *1/*17; CYP2D6 *4/*4; SLCO1B1 *1/*1; VKORC1 G/G a. clopidogrel b. ticagrelor c. prasugrel d. ticlopidine

d. ticlopidine

someone with SLC01B1 *1/*5 or *1/*15 have what kind of function

decreased

a person w a polymorphism of *1/*15 or *1/*5 would be expected to be what kind of metabolizer for SLCO1B1

decreased function

CYP2C19 *9 is what kind of allele

decreased function allelel decreased CYP219 activity avoid clopidogrel

MHC has a major role in

determining whether transplanted tissue will be histocompatible or histoincompatible

the greatest benefit of gentic testing is done at what time in course of tx

early

A genetic test is being evaluated that may predict a severe adverse drug reaction. The HLA allele HLA-C*3101 has been associated with Stevens-Johnson syndrome (SJS) from naproxen. A study is conducted to determine the ability of HLA-C*3101 testing to predict naproxen-induced SJS. In the table below are the number of patients in the study by SJS status and HLA allele test result. HLA-C*3101 testing predicts naproxen-induced SJS well enough to recommend clinical testing before naproxen administration.

false

Multiple randomized controlled trials have been published which show that use of genotype-guided warfarin testing improves patient outcomes, including prevention of PE and DVT. T/F

false

true/ or false CPIC recommends when to genotype

false assume already genotyped when maing therapeutic decisions

for a person who has SLCO1B1 polymorphism of *5/*15 and qualifies for low intensity statin which option has the lowest SAMS risk?

fluvastatin 20-40 mg pravastatin 10-20 mg

components fo Class 1 MHC

involved in regulation of antiviral immune responses found on all nucleated cells mediates immune responses against endogenous antigens MHC Class 1 presents peptides that are 8-10 amino acids and will then be recognized by cytotoxic T cells

people with *2 and *3 mutation of CYP2C19 allele will have more or less active form of plavix?

less active form, need different an antiplatelet

for poor SLCO1B1 function what SAMS risk is acceptable

low

for decreased SLCO1B1 function what SAMS risk is acceptable

moderate

for the international warfarin pharmacogenetics consortium, what must occur with the output of the algorithm to compute the weekly dose in mg

must be squared

should statin therapy be discontinued or avoided based on genotype results

no

can you increase the dose of clopidogrel based on genotype?

no, not viable

fluvastatin max dose for SLCO1B1 decreased function

none

pravastatin max dose for SLCO1B1 decreased function

none

rosuvastatin max dose for SLCO1B1 decreased function

none

CYP2C19 *3 is what type of genotype

nonsense premature stop codon dec activity

someone with SLC01B1 *5/*15 have what kind of function

poor

a person w a polymorphism of *5/*15 would be expected to be what kind of metabolizer for SLCO1B1

poor function w over 4 fold increased risk of myopathy per copy of allele (w simvastatin 80 mg)

for pts with previous stroke/ TIA what cannot be used?

prasugrel

what are contraindications to clopidogrel use

prior TIA/ stroke; active bleeding (e.g. peptic ulcer, intracranial hemorrhage)

if genotype testing is done prior to PCI

rapid turnaround time required

for a person who has SLCO1B1 polymorphism of *5/*15 and qualifies for high intensity statin which option has the lowest SAMS risk?

rosuvastatin 20 mg

CYP2C19 *2 is what type of genotype

splice site polymorphism dec activity

for an ultrarapid, rapid, normal metabolizer of CYP2C19 what is the recommendation of clopidogrel

standard dose clopidogrel (75 mg daily)

define major histocompatibity complex -MHC

tightly linked cluster of genes whose products are associated w intracellular recognition and self/non-slef discrimination -major role in determining whether transplanted tissue will be histocompatible or histoincompatible

what are things to remember for ticagrelor

twice daily med, need to dec aspirin dose to 81 mg daily above 100 mg aspirin reduce efficacy

for someone with a genotype of CYP2C19 *1/*1, *1/*17, *17/*17 what is the CV therapeutic recommendation

use at standard dose of clopidogrel 75 mg/day