NAPLEX Quiz: Pharmacogenomics

What this quiz covers

This quiz focuses on Pharmacogenomics, giving you a quick way to practice the rules, question types, and explanations that matter most for NAPLEX.

How to use this quiz

Try each quiz question before looking at the correct answer. Use the explanations to review missed ideas, then come back to similar questions until the pattern feels familiar.

Question 1

1. Carbamazepine 200 mg by mouth twice daily with slow titration
2. Oxcarbazepine 300 mg by mouth twice daily because it avoids HLA-associated rash risk
3. Gabapentin 300 mg by mouth three times daily as an alternative to carbamazepine (correct answer)
4. Carbamazepine 100 mg by mouth daily because lowering the dose prevents Stevens-Johnson syndrome/toxic epidermal necrolysis

Explanation: This question tests the link between HLA-B15:02 and carbamazepine-induced severe cutaneous reactions like Stevens-Johnson syndrome in certain populations. The key genetic factor is the patient's positive HLA-B15:02 status, which markedly elevates the risk of life-threatening reactions to carbamazepine, especially in Southeast Asians. Gabapentin 300 mg by mouth three times daily as an alternative to carbamazepine is the best choice because it avoids the HLA-associated risk while providing effective treatment for trigeminal neuralgia. Carbamazepine 200 mg twice daily is incorrect as positivity contraindicates its use; oxcarbazepine is suboptimal because it carries a similar, though lower, risk of cross-reactivity. Carbamazepine 100 mg daily is inappropriate as dose reduction does not eliminate the genetic risk of Stevens-Johnson syndrome. A clinical pearl is to screen for HLA-B*15:02 in Asian patients before carbamazepine or oxcarbazepine initiation. For decision-making, if positive, select non-aromatic anticonvulsants like gabapentin or pregabalin, and educate on rash monitoring.

Question 2

1. Start azathioprine at full dose because TPMT deficiency reduces efficacy
2. Avoid azathioprine and recommend an alternative non-thiopurine therapy due to high myelosuppression risk (correct answer)
3. Start azathioprine at 50% of the usual dose and monitor complete blood count weekly
4. Switch to mercaptopurine at standard dose because TPMT genotype applies only to azathioprine

Explanation: This question tests the role of TPMT polymorphisms in thiopurine toxicity, particularly myelosuppression with azathioprine. The key genetic factor is the patient's TPMT *3A/*3A genotype, indicating no functional enzyme activity and high risk of severe toxicity due to accumulation of active metabolites. Avoiding azathioprine and recommending an alternative non-thiopurine therapy is the best choice to prevent life-threatening myelosuppression in this non-functional genotype. Starting at full dose is incorrect as TPMT deficiency increases toxicity, not reduces efficacy; starting at 50% dose is suboptimal for no-function genotypes, where thiopurines are contraindicated. Switching to mercaptopurine is inappropriate as TPMT genotype affects all thiopurines similarly, not just azathioprine. A clinical pearl is to avoid thiopurines entirely in TPMT poor metabolizers and consider biologics or other immunosuppressants for inflammatory bowel disease. For decision-making, genotype TPMT before thiopurine initiation and adjust doses downward for intermediate metabolizers while monitoring blood counts closely.

Question 3

1. Venlafaxine extended-release 75 mg orally daily (correct answer)
2. Paroxetine 60 mg orally daily
3. Fluoxetine 20 mg orally daily
4. Amitriptyline 50 mg orally at bedtime

Explanation: This question evaluates antidepressant selection based on CYP2D6 metabolizer status. The patient is a CYP2D6 ultrarapid metabolizer currently on paroxetine, a CYP2D6 substrate that likely has reduced efficacy due to increased metabolism. Venlafaxine extended-release 75 mg daily is the best choice because it undergoes minimal CYP2D6 metabolism (primarily metabolized by CYP3A4) and would provide more consistent drug levels in an ultrarapid metabolizer. Paroxetine and fluoxetine are extensively metabolized by CYP2D6 and would likely fail due to rapid clearance, while amitriptyline (a tricyclic antidepressant also metabolized by CYP2D6) would have unpredictable effects and higher side effect burden. The clinical principle is that CYP2D6 ultrarapid metabolizers often experience treatment failure with CYP2D6-dependent antidepressants and should preferentially receive antidepressants metabolized by other pathways like venlafaxine, mirtazapine, or bupropion.

Question 4

1. Continue allopurinol and add cetirizine because HLA-B*58:01 is not clinically actionable
2. Discontinue allopurinol immediately and avoid future allopurinol use due to high risk of severe cutaneous adverse reactions (correct answer)
3. Reduce allopurinol to 100 mg daily because the reaction is dose-dependent in HLA-B*58:01 carriers
4. Switch to febuxostat only after confirming CYP2C19 poor metabolizer status

Explanation: This question evaluates recognition of HLA-B58:01-associated allopurinol hypersensitivity syndrome. The patient presents with classic features of allopurinol hypersensitivity syndrome (fever, rash, eosinophilia, liver enzyme elevation) and is HLA-B58:01 positive, which increases the risk of severe cutaneous adverse reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis by 80-100 fold. Discontinuing allopurinol immediately and avoiding future use is the best choice because continued exposure can lead to life-threatening progression of the hypersensitivity reaction. Dose reduction does not mitigate the immune-mediated reaction in HLA-B58:01 carriers, and the reaction is not dose-dependent. The clinical principle is that HLA-B58:01 positive patients, particularly those of Asian descent or with chronic kidney disease, should avoid allopurinol entirely, and febuxostat represents a safe alternative for gout management in these patients.

Question 5

1. Continue codeine/acetaminophen 30 mg/300 mg by mouth every 6 hours as needed because it is a prodrug and will be safer
2. Switch to tramadol 50 mg by mouth every 6 hours as needed for pain
3. Switch to morphine immediate-release 15 mg by mouth every 4 hours as needed for pain (correct answer)
4. Switch to hydrocodone/acetaminophen 5 mg/325 mg by mouth every 6 hours as needed for pain

Explanation: This question tests the impact of CYP2D6 polymorphisms on opioid prodrug activation and analgesic efficacy. The key genetic factor is the patient's CYP2D6 *4/*4 genotype, classifying them as a poor metabolizer with minimal enzyme activity. Switching to morphine immediate-release 15 mg by mouth every 4 hours as needed is the best choice because morphine is an active opioid that does not require CYP2D6-mediated conversion for efficacy, ensuring adequate pain relief in this poor metabolizer. Continuing codeine/acetaminophen is incorrect as codeine is a prodrug reliant on CYP2D6 for activation to morphine, leading to suboptimal analgesia in poor metabolizers; switching to tramadol is suboptimal because it also depends on CYP2D6 for conversion to its active metabolite O-desmethyltramadol. Switching to hydrocodone/acetaminophen is inappropriate as hydrocodone similarly requires CYP2D6 activation to hydromorphone, resulting in reduced efficacy. A clinical pearl is that for CYP2D6 poor metabolizers, select active opioids like morphine or fentanyl over prodrugs such as codeine, tramadol, or hydrocodone to optimize pain management. When applying pharmacogenomics, always consider the metabolic pathway of the drug and match it to the patient's genotype to avoid therapeutic failure or toxicity.

Question 6

1. Dispense allopurinol 100 mg by mouth daily and counsel to stop if mild rash occurs
2. Recommend febuxostat as an alternative urate-lowering therapy and avoid allopurinol (correct answer)
3. Increase allopurinol starting dose to 300 mg by mouth daily to reduce flare risk
4. Order CYP2C9 testing before starting allopurinol to prevent severe cutaneous reactions

Explanation: This question tests the association between HLA-B58:01 and allopurinol-induced severe cutaneous adverse reactions (SCARs) like Stevens-Johnson syndrome. The key genetic factor is the patient's positive HLA-B58:01 status, which significantly increases the risk of hypersensitivity reactions to allopurinol, particularly in Asian populations. Recommending febuxostat as an alternative urate-lowering therapy and avoiding allopurinol is the best choice to prevent potentially life-threatening SCARs in this high-risk genotype. Dispensing allopurinol 100 mg daily is incorrect as HLA-B58:01 positivity contraindicates its use, and stopping for mild rash does not mitigate severe risks; increasing to 300 mg daily is suboptimal because it heightens exposure and reaction risk without addressing the genetic predisposition. Ordering CYP2C9 testing is irrelevant as it pertains to warfarin metabolism, not allopurinol hypersensitivity. A transferable pearl is to screen for HLA-B58:01 before allopurinol initiation in at-risk ethnic groups like Asians. In practice, if positive, select alternatives like febuxostat or probenecid, and educate patients on early signs of hypersensitivity for any urate-lowering therapy.

Question 7

1. Start warfarin 10 mg orally once daily and check INR in 5–7 days
2. Start warfarin 5 mg orally once daily and check INR in 3–5 days
3. Start warfarin 0.5–2 mg orally once daily with close INR monitoring and slower titration (correct answer)
4. Avoid warfarin due to CYP2C9 genotype and start rivaroxaban 20 mg orally once daily solely for pharmacogenomic reasons

Explanation: This question tests the application of CYP2C9 and VKORC1 pharmacogenomics to warfarin dosing. The patient has CYP2C9 *3/*3 (poor metabolizer) and VKORC1 -1639 A/A (increased warfarin sensitivity), both of which significantly reduce warfarin dose requirements. Starting warfarin 0.5-2 mg daily with close INR monitoring and slower titration is the best choice because patients with this genotype combination have approximately 75-80% reduction in warfarin dose requirements compared to wild-type patients. Standard dosing (5-10 mg) would lead to supratherapeutic INRs and bleeding risk, while avoiding warfarin solely for pharmacogenomic reasons is inappropriate when the drug can be safely used with dose adjustment. The clinical pearl is that patients with combined CYP2C9 poor metabolizer status and VKORC1 variant alleles require the most dramatic warfarin dose reductions, often needing less than 2 mg daily to achieve therapeutic INR.

Question 8

1. Genetic testing for CYP2C19 is required before apixaban because it is a prodrug
2. Routine pharmacogenomic testing is not recommended for apixaban dosing; kidney function, age, and interacting drugs are more important (correct answer)
3. HLA-B*57:01 testing predicts apixaban bleeding risk and should be ordered
4. VKORC1 genotype determines apixaban dose and should be checked prior to discharge

Explanation: This question tests understanding of pharmacogenomic relevance to direct oral anticoagulants (DOACs). The patient asks about genetic testing for apixaban, but routine pharmacogenomic testing is not recommended for apixaban dosing because apixaban is not a prodrug and its metabolism is not significantly affected by genetic polymorphisms. The best counseling point is that kidney function, age, body weight, and drug interactions are the primary determinants of apixaban dosing and safety, not genetic factors. CYP2C19 testing is irrelevant as apixaban is metabolized by CYP3A4/5, HLA-B*57:01 relates to abacavir hypersensitivity not bleeding risk, and VKORC1 affects warfarin not DOAC therapy. The clinical pearl is that unlike warfarin (affected by CYP2C9/VKORC1) or clopidogrel (affected by CYP2C19), DOACs like apixaban do not require pharmacogenomic testing for safe and effective use.

Question 9

1. Continue clopidogrel 75 mg daily because the stent indication outweighs pharmacogenomic considerations
2. Switch clopidogrel to prasugrel 10 mg orally daily (if no contraindications) or ticagrelor 90 mg orally twice daily (correct answer)
3. Add omeprazole 20 mg orally daily to improve clopidogrel activation and reduce gastrointestinal risk
4. Order HLA-B*57:01 testing before continuing clopidogrel due to hypersensitivity risk

Explanation: This question evaluates understanding of CYP2C19 pharmacogenomics in antiplatelet therapy following percutaneous coronary intervention. The patient is a CYP2C19 *2/2 poor metabolizer, which results in significantly reduced conversion of clopidogrel to its active metabolite and inadequate platelet inhibition. Switching to prasugrel 10 mg daily or ticagrelor 90 mg twice daily is the best choice because these P2Y12 inhibitors are not dependent on CYP2C19 for activation and provide consistent antiplatelet effects in poor metabolizers. Continuing clopidogrel despite poor metabolizer status increases the risk of stent thrombosis and recurrent cardiovascular events. Adding omeprazole would further reduce clopidogrel activation through CYP2C19 inhibition, and HLA-B57:01 testing is irrelevant to clopidogrel therapy. The key principle is that CYP2C19 poor metabolizers receiving clopidogrel after PCI should be switched to alternative P2Y12 inhibitors to ensure adequate antiplatelet protection.

Question 10

1. Increase amitriptyline to 50 mg nightly because poor metabolizers have reduced effect
2. Switch to nortriptyline at standard dose because CYP2D6 phenotype does not affect tricyclic antidepressants
3. Consider an alternative agent (for example, duloxetine) or substantially reduce amitriptyline dose with close monitoring (correct answer)
4. Add omeprazole to improve amitriptyline tolerability in CYP2D6 poor metabolizers

Explanation: This question tests the effects of CYP2D6 and CYP2C19 polymorphisms on tricyclic antidepressant metabolism and adverse effects. The key genetic factor is the patient's CYP2D6 poor metabolizer status, resulting in reduced amitriptyline metabolism and increased risk of anticholinergic effects like dry mouth and dizziness. Considering an alternative agent like duloxetine or substantially reducing amitriptyline dose with close monitoring is the best choice to alleviate side effects while treating neuropathic pain effectively. Increasing to 50 mg is incorrect as poor metabolizers have higher exposure, not reduced effect, requiring lower doses; switching to nortriptyline is suboptimal because CYP2D6 affects all tricyclics similarly. Adding omeprazole is irrelevant as it inhibits CYP2C19, potentially worsening exposure. A clinical pearl is to avoid or dose-reduce tricyclics in CYP2D6 poor metabolizers, preferring SNRIs like duloxetine. For decision-making, integrate genotype with symptom monitoring to optimize antidepressant therapy and minimize toxicity.

Question 11

1. Increase phenytoin dose because CYP2C9 poor metabolizers have low phenytoin exposure
2. Reduce phenytoin maintenance dose and titrate cautiously with level monitoring (correct answer)
3. Continue current dose and add carbamazepine because CYP2C9 genotype is not clinically relevant
4. Switch to clopidogrel because CYP2C9 genotype predicts antiplatelet response

Explanation: This question tests the influence of CYP2C9 polymorphisms on phenytoin metabolism and toxicity risk. The key genetic factor is the patient's CYP2C9 *3/*3 poor metabolizer genotype, leading to decreased clearance and higher phenytoin levels, causing symptoms like nystagmus and ataxia. Reducing the phenytoin maintenance dose and titrating cautiously with level monitoring is the best choice to restore therapeutic levels and resolve toxicity in this poor metabolizer. Increasing the dose is incorrect as poor metabolizers have high, not low, exposure; continuing the dose and adding carbamazepine ignores the genotype's relevance to phenytoin. Switching to clopidogrel is irrelevant as CYP2C9 affects anticoagulants and anticonvulsants, not antiplatelets directly. A transferable pearl is to initiate phenytoin at 50-70% lower doses in CYP2C9 poor metabolizers and use corrected levels for hypoalbuminemia. In practice, always monitor phenytoin concentrations and adjust based on genotype, ethnicity, and clinical response for seizure control.

Question 12

1. Increase mercaptopurine dose because intermediate NUDT15 status predicts reduced efficacy
2. Reduce mercaptopurine dose substantially (e.g., start at a reduced fraction of standard) and titrate based on blood counts due to NUDT15-associated myelotoxicity risk (correct answer)
3. Continue mercaptopurine at the same dose because TPMT is normal and NUDT15 does not affect thiopurines
4. Switch mercaptopurine to azathioprine at an equivalent dose because NUDT15 only impacts mercaptopurine

Explanation: This question evaluates understanding of NUDT15 pharmacogenomics in thiopurine therapy. The patient is a NUDT15 intermediate metabolizer with severe neutropenia after starting mercaptopurine, indicating NUDT15-associated myelotoxicity. Reducing mercaptopurine dose substantially (typically to 30-50% of standard dose) and titrating based on blood counts is the best approach because NUDT15 variants reduce thiopurine metabolism leading to accumulation of active metabolites and bone marrow suppression. NUDT15 affects both mercaptopurine and azathioprine equally, so switching between them provides no benefit. The patient's normal TPMT status doesn't protect against NUDT15-related toxicity, as these are independent pathways. The clinical principle is that NUDT15 testing is particularly important in Asian populations (where variant allele frequency can exceed 10%) and intermediate metabolizers require 30-50% dose reductions while poor metabolizers may need 80-90% reductions or alternative therapy.

Question 13

1. Initiate warfarin 7.5 mg by mouth daily because CYP2C9 *3/*3 requires higher doses
2. Initiate warfarin 0.5–2 mg by mouth daily with close INR monitoring (correct answer)
3. Initiate warfarin 5 mg by mouth daily because VKORC1 A/A predicts warfarin resistance
4. Avoid warfarin because VKORC1 genotype predicts lack of efficacy; use aspirin instead

Explanation: This question tests the combined effects of CYP2C9 and VKORC1 polymorphisms on warfarin dosing requirements. The key genetic factors are the patient's CYP2C9 *3/*3 (poor metabolizer) and VKORC1 -1639 A/A genotypes, both associated with increased warfarin sensitivity and lower dose needs. Initiating warfarin at 0.5–2 mg by mouth daily with close INR monitoring is the best choice as this reduced starting dose accounts for the heightened sensitivity, minimizing bleeding risk while allowing careful titration. Initiating at 7.5 mg daily is incorrect because CYP2C9 *3/*3 requires lower, not higher, doses due to impaired metabolism; initiating at 5 mg daily is suboptimal as VKORC1 A/A predicts sensitivity, not resistance, necessitating lower doses. Avoiding warfarin is inappropriate since VKORC1 A/A indicates sensitivity but not lack of efficacy, and aspirin alone may not suffice for deep vein thrombosis. A clinical pearl is to use pharmacogenomic-guided algorithms incorporating CYP2C9, VKORC1, and clinical factors to estimate initial warfarin doses. For decision-making, always combine genotyping with frequent INR monitoring, especially in sensitive genotypes, to achieve therapeutic anticoagulation safely.

Question 14

1. Initiate tamsulosin at a lower dose or consider an alternative alpha-1 blocker with careful monitoring for orthostatic hypotension (correct answer)
2. Initiate tamsulosin at a higher dose because CYP2D6 poor metabolizers have lower exposure
3. Avoid all alpha-1 blockers because CYP2D6 poor metabolizers will have treatment failure
4. Use standard tamsulosin dosing because CYP2D6 only affects codeine and not other drugs

Explanation: This question tests the impact of CYP2D6 polymorphisms on tamsulosin metabolism and adverse effects in benign prostatic hyperplasia. The key genetic factor is the patient's CYP2D6 poor metabolizer status, resulting in higher tamsulosin exposure and increased risk of orthostatic hypotension or dizziness. Initiating tamsulosin at a lower dose or considering an alternative alpha-1 blocker with careful monitoring is the best choice to manage symptoms safely. Initiating at a higher dose is incorrect as poor metabolizers have higher, not lower, exposure; avoiding all alpha-1 blockers overstates the risk, as alternatives like alfuzosin are less CYP2D6-dependent. Standard dosing ignores the genotype's relevance to tamsulosin. A clinical pearl is to reduce tamsulosin doses in CYP2D6 poor metabolizers and monitor blood pressure. For decision-making, select agents with minimal CYP2D6 involvement in poor metabolizers, integrating vital signs for personalized therapy.

Question 15

1. Tamoxifen 20 mg by mouth daily and continue bupropion because CYP2D6 poor metabolizers have higher endoxifen levels
2. Tamoxifen 40 mg by mouth daily to overcome CYP2D6 poor metabolism
3. Consider an alternative endocrine therapy (for example, an aromatase inhibitor if appropriate) or address CYP2D6 inhibition/phenotype to optimize therapy (correct answer)
4. Switch bupropion to omeprazole because CYP2D6 poor metabolizers should avoid proton pump inhibitors

Explanation: This question evaluates the impact of CYP2D6 polymorphisms on tamoxifen bioactivation and therapeutic efficacy in breast cancer treatment. The key patient-specific genetic factor is the CYP2D6 *4/*4 genotype, classifying the patient as a poor metabolizer, which impairs conversion of tamoxifen to its active metabolite endoxifen. Considering an alternative endocrine therapy or addressing CYP2D6 inhibition is the best choice because poor metabolizers may have reduced tamoxifen efficacy, and bupropion's CYP2D6 inhibition exacerbates this, necessitating optimization. Recommending standard-dose tamoxifen with continued bupropion is incorrect as poor metabolizers actually have lower endoxifen levels, not higher, and increasing to 40 mg daily is suboptimal without strong evidence to overcome poor metabolism fully. Switching bupropion to omeprazole is misguided because omeprazole inhibits CYP2C19, not CYP2D6, and the advice on proton pump inhibitors is irrelevant here. Clinically, always assess CYP2D6 status and drug interactions before tamoxifen initiation to maximize endoxifen exposure and outcomes. Use a framework that integrates genotyping with medication reconciliation to guide personalized endocrine therapy in hormone receptor-positive breast cancer.

Question 16

1. Recommend paroxetine because CYP2C19 poor metabolizers have reduced paroxetine exposure
2. Recommend standard-dose citalopram because CYP2C19 poor metabolizers have increased clearance
3. Recommend sertraline at a reduced starting dose with slower titration than usual (correct answer)
4. Recommend escitalopram at a higher starting dose to overcome reduced activation

Explanation: This question tests the influence of CYP2C19 polymorphisms on selective serotonin reuptake inhibitor (SSRI) metabolism and dosing adjustments. The key genetic factor is the patient's CYP2C19 *2/*2 genotype, indicating poor metabolizer status with reduced enzyme activity leading to higher drug exposure. Recommending sertraline at a reduced starting dose with slower titration is the best choice because sertraline is less dependent on CYP2C19 for metabolism compared to other SSRIs, but poor metabolizers may still require cautious dosing to minimize adverse effects like sedation and nausea. Recommending paroxetine is incorrect as CYP2C19 poor metabolizers have increased paroxetine exposure, not reduced, heightening toxicity risk; recommending standard-dose citalopram is suboptimal because poor metabolizers have decreased clearance, not increased, leading to higher exposure and side effects. Recommending escitalopram at a higher dose is inappropriate as poor metabolizers experience increased exposure, requiring lower doses rather than higher to avoid adverse effects. A transferable pearl is to prioritize SSRIs with minimal CYP2C19 involvement, like sertraline or fluoxetine, in poor metabolizers while starting low and titrating slowly. In practice, integrate pharmacogenomic data with patient history, such as prior adverse reactions, to guide antidepressant selection and dosing for optimal outcomes.

Question 17

1. Restart simvastatin 40 mg by mouth daily because SLCO1B1 variants reduce myopathy risk
2. Switch to pravastatin at a moderate intensity dose and monitor for muscle symptoms (correct answer)
3. Switch to simvastatin 80 mg by mouth daily to achieve LDL reduction despite genotype
4. Switch to clopidogrel because SLCO1B1 predicts response to antiplatelet therapy

Explanation: This question tests the role of SLCO1B1 polymorphisms in statin-induced myopathy risk. The key genetic factor is the patient's SLCO1B1 c.521T>C (TC) genotype, indicating decreased transporter function and increased simvastatin exposure, heightening myopathy risk. Switching to pravastatin at a moderate intensity dose and monitoring for muscle symptoms is the best choice as pravastatin is less affected by SLCO1B1, reducing myopathy risk while achieving lipid goals. Restarting simvastatin 40 mg is incorrect as SLCO1B1 variants increase, not reduce, myopathy risk; switching to simvastatin 80 mg is suboptimal because higher doses exacerbate risk in decreased function genotypes. Switching to clopidogrel is irrelevant as SLCO1B1 affects statins, not antiplatelets. A transferable pearl is to avoid high-dose simvastatin in SLCO1B1 decreased function carriers and prefer pravastatin or rosuvastatin. In practice, combine genotyping with creatine kinase monitoring and patient symptoms to guide statin selection and dosing.

Question 18

1. BCR-ABL1 mutation status (correct answer)
2. HLA-B*57:01
3. SLCO1B1 c.521T>C
4. VKORC1 -1639G>A

Explanation: This question tests genetic markers guiding tyrosine kinase inhibitor response in chronic myeloid leukemia. The key genetic factor for imatinib response is BCR-ABL1 mutation status, as specific mutations like T315I can confer resistance, unlike the provided CYP2C19 genotype which affects other drugs. BCR-ABL1 mutation status is the best choice because it directly predicts imatinib efficacy and guides switches to alternatives like dasatinib or nilotinib in resistant cases. HLA-B*57:01 is incorrect as it relates to abacavir hypersensitivity; SLCO1B1 c.521T>C affects statin myopathy risk. VKORC1 -1639G>A pertains to warfarin dosing. A transferable pearl is to test for BCR-ABL1 mutations in suboptimal CML responders to select optimal TKIs. In practice, integrate mutation profiling with quantitative PCR monitoring to personalize therapy and improve outcomes in targeted oncology.

Question 19

1. Start at full dose because TPMT intermediate metabolizers have lower myelosuppression risk
2. Start at a reduced dose (for example, 30–70% of target) and titrate based on blood counts (correct answer)
3. Avoid mercaptopurine because TPMT intermediate metabolizers cannot convert it to active metabolites
4. Increase dose because TPMT intermediate metabolizers have increased clearance

Explanation: This question tests TPMT polymorphisms and their impact on mercaptopurine dosing in inflammatory bowel disease. The key genetic factor is the patient's TPMT *1/*3A intermediate metabolizer status, leading to partial enzyme deficiency and increased myelosuppression risk at standard doses. Starting at a reduced dose (for example, 30–70% of target) and titrating based on blood counts is the best choice to balance efficacy and safety in this genotype. Starting at full dose is incorrect as intermediate metabolizers have higher, not lower, toxicity risk; avoiding mercaptopurine is suboptimal since adjusted doses are typically tolerated. Increasing the dose is wrong because intermediate metabolizers have decreased, not increased, clearance. A clinical pearl is to reduce thiopurine doses by 30-70% in TPMT intermediate metabolizers and monitor CBC frequently. For decision-making, combine TPMT genotyping with metabolite monitoring to optimize dosing and prevent toxicity in long-term therapy.

Question 20

1. Nicotine patch at standard dose because slow nicotine metabolizers may do well with nicotine replacement therapy (correct answer)
2. High-dose nicotine patch plus gum because slow nicotine metabolizers require aggressive dosing
3. Clopidogrel because CYP2A6 predicts response to antiplatelet therapy
4. Codeine because slow nicotine metabolizers have improved opioid analgesia

Explanation: This question tests the role of CYP2A6 polymorphisms in nicotine metabolism and smoking cessation strategies. The key genetic factor is the patient's CYP2A6 decreased function (slow metabolizer) status, leading to slower nicotine clearance and potentially better response to standard nicotine replacement therapy. Nicotine patch at standard dose is the best choice because slow metabolizers may achieve adequate levels with usual dosing, aiding cessation without excessive replacement. High-dose patch plus gum is incorrect as slow metabolizers do not require aggressive dosing due to prolonged exposure; clopidogrel is irrelevant to smoking cessation. Codeine is unrelated and risky in varying metabolizers. A transferable pearl is that CYP2A6 slow metabolizers often succeed with nicotine replacement, while rapid metabolizers may need varenicline. In practice, tailor cessation aids by genotype, incorporating behavioral support for all patients.