PGx Exam 2: CONDENSED Meds + SEs

Clopidogrel in a CYP2C19 ultrarapid or rapid metabolizer, what happens and what is the recommendation?

Increased active metabolite and platelet inhibition, standard dose

Clopidogrel in a CYP2C19 intermediate metabolizer, what happens and what is the recommendation?

Reduced activation, use prasugrel or ticagrelor at standard dose if no contraindication

Clopidogrel in a CYP2C19 poor metabolizer, what happens and what is the recommendation?

Loss of function, avoid clopidogrel and use prasugrel or ticagrelor

What are the risks of clopidogrel in a CYP2C19 poor metabolizer?

Stent thrombosis, MI, stroke

What is the boxed warning for clopidogrel in CYP2C19 poor metabolizers?

No clopidogrel effect

What is the main side effect of prasugrel or ticagrelor?

Bleeding

Omeprazole or esomeprazole in a CYP2C19 ultrarapid or rapid metabolizer, what happens and what is the recommendation?

Decreased PPI levels, treatment failure, increase dose 50-100%

Omeprazole or esomeprazole in a CYP2C19 normal metabolizer, what is the recommendation?

Standard dose, for chronic therapy longer than 12 weeks with efficacy consider 50% reduction

Omeprazole or esomeprazole in a CYP2C19 intermediate or poor metabolizer, what is the recommendation?

Standard dose, for chronic therapy longer than 12 weeks with efficacy consider 50% reduction (poor metabolizer same as intermediate)

Why avoid omeprazole or esomeprazole with clopidogrel?

They reduce clopidogrel activation, use pantoprazole instead

Voriconazole in a CYP2C19 ultrarapid or rapid metabolizer, what is the recommendation?

Use an alternative, isavuconazole, liposomal amphotericin B, or posaconazole

Voriconazole in a CYP2C19 intermediate metabolizer, what is the recommendation?

Lower dose with therapeutic drug monitoring, trough 0.5-6 mg/L

Voriconazole in a CYP2C19 poor metabolizer, what is the recommendation?

Use an alternative, or lower dose with therapeutic drug monitoring if voriconazole is still preferred

Side effects of voriconazole?

Hepatotoxicity, neurotoxicity (hallucinations, encephalopathy), visual disturbances, photosensitivity, rash, periostitis

Citalopram or escitalopram in a CYP2C19 ultrarapid or rapid metabolizer, what is the recommendation?

Use an alternative not metabolized by CYP2C19, or start standard dose and switch if no response

Citalopram or escitalopram in a CYP2C19 poor metabolizer, what is the recommendation?

Consider 50% dose reduction with titration, or use an alternative

Sertraline in a CYP2C19 ultrarapid or rapid metabolizer, what is the recommendation?

Standard starting dose

Sertraline in a CYP2C19 poor metabolizer, what is the recommendation?

Lower starting dose, slower titration, 25% reduction of standard maintenance dose, or select an alternative antidepressant

Side effects of sertraline?

Insomnia, headache, GI upset, sexual dysfunction, QT prolongation, arrhythmia, serotonin syndrome

What are the CYP2C19 inhibitors?

Fluvoxamine, fluoxetine, voriconazole, ketoconazole, omeprazole, esomeprazole, lansoprazole, ticlopidine

What is the CYP2C19 inducer and what phenotype does it shift toward?

Rifampin, shifts toward ultrarapid metabolizer

Codeine in a CYP2D6 ultrarapid metabolizer, what is the recommendation and why?

Avoid, morphine forms too fast, risk of toxicity

Codeine in a CYP2D6 intermediate metabolizer, what is the recommendation?

Reduced morphine, label dosing, if no response use an alternative

Codeine in a CYP2D6 poor metabolizer, what is the recommendation and why?

Avoid, insufficient analgesia

Side effects of codeine?

Sedation, respiratory depression, death

Who should avoid codeine regardless of metabolizer status?

Children and breastfeeding patients

Tramadol in a CYP2D6 ultrarapid metabolizer, what is the recommendation and why?

Avoid, toxicity from excess M1

Tramadol in a CYP2D6 intermediate metabolizer, what is the recommendation?

Reduced M1, label dosing or alternative if no response

Tramadol in a CYP2D6 poor metabolizer, what happens and what is the recommendation?

Poor analgesia from low M1, use an alternative

Hydrocodone in a CYP2D6 ultrarapid metabolizer, what is the recommendation?

No recommendation, minimal data

Hydrocodone in a CYP2D6 intermediate metabolizer, what is the recommendation?

Label dosing, if no response use a non-codeine, non-tramadol opioid

Hydrocodone in a CYP2D6 poor metabolizer, what is the recommendation?

Same as intermediate metabolizer

Paroxetine in a CYP2D6 ultrarapid metabolizer, what is the recommendation?

Do not use, use an alternative

Paroxetine in a CYP2D6 intermediate metabolizer, what is the recommendation?

25% lower starting dose, slower titration

Paroxetine in a CYP2D6 poor metabolizer, what is the recommendation?

50% lower starting and maintenance dose

Fluvoxamine in a CYP2D6 intermediate or poor metabolizer, what is the recommendation?

Label dosing for intermediate, 25-50% lower starting dose with slower titration or alternative for poor

Vortioxetine in a CYP2D6 ultrarapid metabolizer, what is the recommendation?

Use an alternative, or start standard and titrate, target dose may need 50% or more increase

Vortioxetine in a CYP2D6 intermediate metabolizer, what is the recommendation?

Label dosing

Vortioxetine in a CYP2D6 poor metabolizer, what is the recommendation?

Start at 50% of starting dose (5 mg), titrate to max 10 mg, or use an alternative

Venlafaxine in a CYP2D6 ultrarapid or intermediate metabolizer, what is the recommendation?

No change

Venlafaxine in a CYP2D6 poor metabolizer, what is the recommendation?

Do not use, adverse effects in poor metabolizers

Atomoxetine in a CYP2D6 intermediate metabolizer, what happens and what is the recommendation?

Higher concentration, adjust dose by score

Atomoxetine in a CYP2D6 poor metabolizer, what happens and what is the recommendation?

Significantly higher concentration, lower dose and monitor

Side effects of atomoxetine?

Insomnia, weight loss, constipation, xerostomia, depression, tremor, sedation

Aripiprazole in a CYP2D6 poor metabolizer, what is the recommendation?

FDA recommends reducing oral dose by 50%

Aripiprazole in a CYP2D6 ultrarapid metabolizer, what is the recommendation?

No FDA dose adjustment

Side effects of aripiprazole?

Weight gain, hyperglycemia, akathisia, EPS, sedation

Ondansetron in a CYP2D6 ultrarapid metabolizer, what is the recommendation?

Use an alternative not mainly metabolized by CYP2D6, such as granisetron

Ondansetron in intermediate or poor metabolizers, what is the recommendation?

Limited data, use label dosing

Side effects of ondansetron?

Headache, constipation, transient LFT increase, QT prolongation (serious)

Which TCAs are CYP2D6 only?

Secondary TCAs, nortriptyline and desipramine

Which TCAs are affected by both CYP2D6 and CYP2C19?

Tertiary TCAs, amitriptyline, imipramine, trimipramine, doxepin, clomipramine

Secondary TCA in a CYP2D6 ultrarapid metabolizer, what is the recommendation?

Avoid, lack of efficacy, if warranted titrate to higher target with TDM

Secondary TCA in a CYP2D6 intermediate metabolizer, what is the recommendation?

Reduce starting dose 25%, use TDM

Secondary TCA in a CYP2D6 poor metabolizer, what is the recommendation?

Avoid, toxicity, if warranted reduce starting dose 50%, use TDM

Tertiary TCA in a CYP2C19 ultrarapid or rapid metabolizer, what is the recommendation?

Avoid, use a secondary TCA, suboptimal response

Tertiary TCA in a CYP2C19 poor metabolizer, what is the recommendation?

Avoid, or reduce starting dose 50% if warranted

Amitriptyline, when should you use an alternative?

CYP2C19 ultrarapid, rapid, or poor metabolizer, or CYP2D6 ultrarapid or poor metabolizer

Amitriptyline with CYP2D6 intermediate plus CYP2C19 normal or intermediate, what is the recommendation?

Reduce dose 25%

Amitriptyline with CYP2D6 poor plus CYP2C19 normal or intermediate, what is the recommendation?

Reduce dose 50% if no alternative

What is phenoconversion?

A change in phenotype without a change in genotype, caused by drug interactions, disease, or inflammation

What are the strong CYP2D6 inhibitors?

Fluoxetine, paroxetine, bupropion, terbinafine, quinidine

Example of phenoconversion with CYP2D6?

A normal metabolizer on bupropion converts to a poor metabolizer, so avoid codeine

What does atazanavir do to UGT1A1?

Inhibits UGT1A1

UGT1A1 28/28 or 6/6 (poor metabolizer) with atazanavir, what happens and what is the recommendation?

Raises bilirubin, causing jaundice and drug discontinuation, consider an alternative

What is Gilbert syndrome?

Homozygous reduced-function UGT1A1, causing mild hyperbilirubinemia that worsens with fasting or infection

TPMT or NUDT15 intermediate metabolizer, malignancy (6-MP), what is the dose recommendation?

Reduce 30-80%

TPMT or NUDT15 intermediate metabolizer, non-malignancy (azathioprine), what is the dose recommendation?

Reduce 30-80%

TPMT and NUDT15 both intermediate metabolizers, malignancy (6-MP), what is the dose recommendation?

Reduce 20-50%

TPMT or NUDT15 poor metabolizer, malignancy (6-MP), what is the dose recommendation?

Reduce to 10% of dose, given 3 times per week

TPMT or NUDT15 poor metabolizer, non-malignancy (azathioprine), what is the recommendation?

Use an alternative agent

Side effects of azathioprine and 6-MP?

Bone marrow suppression, leukopenia, thrombocytopenia, anemia (myelotoxicity)

Are TPMT and NUDT15 recommendations for starting dose or maintenance?

Starting dose only

How long to reach steady state with TPMT or NUDT15 variants?

2-4 weeks for intermediate metabolizers, 4-6 weeks for poor metabolizers

When both TPMT and NUDT15 results are available, which result do you follow?

The most conservative result

NAT2 slow acetylators (poor metabolizers) and hydralazine, what happens?

Higher drug levels and greater risk of adverse effects, including drug-induced lupus-like syndrome

NAT2 poor metabolizer, hydralazine dosing?

Start at 40-75 mg total daily dose, titrate carefully, use caution at 200 mg/day or more

What is phase II metabolism?

Conjugation of drugs or metabolites with endogenous substrates to increase water solubility and promote excretion

What is the rate-limiting enzyme for fluoropyrimidines?

DPD, encoded by DPYD

DPYD activity score 2 (normal), what is the recommendation and risk?

Label dosing, normal risk

DPYD activity score 1 or 1.5 (intermediate), what is the recommendation and risk?

Reduce starting dose 50%, then titrate by monitoring, risk of severe or fatal toxicity

DPYD activity score 0 or 0.5 (poor), what is the recommendation?

Avoid, if no alternative and score is 0.5, use less than 25% of dose

What happens with complete DPD deficiency?

Severe or fatal toxicity

Side effects of fluoropyrimidines (5-FU, capecitabine)?

Neutropenia, myelosuppression, severe diarrhea, mucositis or stomatitis, hand-foot syndrome, nausea and vomiting

When should DPYD be tested before starting Xeloda?

Before starting, unless treatment is urgent

ABCG2 (BCRP) reduced function, what happens?

Higher absorption and reduced excretion of rosuvastatin, more diarrhea with irinotecan and gefitinib

ABCC1 (MRP1) CC or TT genotype, what happens?

Less methotrexate efflux, linked to better methotrexate response in psoriasis

ABCB1 (MDR1, P-gp) reduced function, what is affected?

Absorption of digoxin, methotrexate, nevirapine, atazanavir, fentanyl, methadone

SLCO1B1 decreased or poor function, which statins should be avoided?

Simvastatin and lovastatin

SLCO1B1 decreased or poor function, which statins are dose-reduced?

Atorvastatin, pravastatin, fluvastatin, and rosuvastatin (poor function)

Rosuvastatin with decreased ABCG2 function, what is the maximum starting dose?

20 mg

Rosuvastatin with poor ABCG2 function, what is the maximum dose?

10 mg

Fluvastatin with CYP2C9 poor metabolizer, what is the maximum starting dose?

20 mg

Fluvastatin with CYP2C9 intermediate metabolizer, what is the maximum starting dose?

40 mg

How does cyclosporine affect simvastatin?

Raises simvastatin AUC 3-8 fold by inhibiting SLCO1B1 and CYP3A4

Main side effect with reduced SLCO1B1 function?

Statin-associated musculoskeletal symptoms (myopathy)

Sertraline in a CYP2C19 intermediate metabolizer, what is the recommendation?

Standard starting dose, consider slower titration and lower maintenance dose

Fluvoxamine in a CYP2D6 ultrarapid metabolizer, what is the recommendation?

No recommendation

What is paroxetine’s role in CYP2D6?

It is an auto-inhibitor of CYP2D6

Side effects of hydrocodone? Side effects of tramadol?

Standard opioid toxicity. Opioid side effects