Pharmacogenomics - NAPLEX

1. Which phenotype corresponds to increased function due to duplication or increased-activity alleles?

   Ultrarapid metabolizer (UM). Gene duplications or gain-of-function variants enhance enzyme activity, accelerating drug metabolism and potentially reducing efficacy.

2. What does the star (*) allele nomenclature represent (for example, CYP2D6*4)?

   A named haplotype (set of variants) within a gene. Star allele nomenclature designates specific combinations of genetic variants that define functional haplotypes in pharmacogenes like CYPs.

3. Which enzyme deficiency increases risk of hemolytic anemia with primaquine or rasburicase?

   G6PD deficiency. G6PD deficiency impairs oxidative stress handling, leading to red blood cell hemolysis upon exposure to oxidizing agents like these drugs.

4. What is the abacavir prescribing action if HLA-B*57:01 is positive?

   Do not use abacavir. Positive HLA-B*57:01 status confers high risk of life-threatening hypersensitivity, contraindicating abacavir use per guidelines.

5. Which HLA allele is associated with carbamazepine-induced SJS/TEN in many Asian ancestries?

   HLA-B*15:02. HLA-B*15:02 is linked to increased SJS/TEN risk in susceptible populations, warranting genetic screening before carbamazepine therapy.

6. What is the CYP2D6-guided recommendation for codeine in ultrarapid metabolizers?

   Avoid codeine due to toxicity risk; use alternative analgesic. Ultrarapid CYP2D6 activity converts codeine to excessive morphine, heightening risks of respiratory depression and overdose.

7. What is the CYP2D6-guided recommendation for codeine in poor metabolizers?

   Avoid codeine due to lack of effect; use alternative analgesic. Poor CYP2D6 metabolizers fail to convert codeine to morphine, resulting in inadequate analgesia and necessitating non-opioid options.

8. What is the definition of pharmacogenomics relevant to drug therapy decisions?

   Use of genetic variation to guide drug choice and dosing. Pharmacogenomics applies genetic information to personalize medication therapy by optimizing efficacy and minimizing adverse effects.

9. What is the allopurinol prescribing action if HLA-B*58:01 is positive?

   Avoid allopurinol; use an alternative urate-lowering therapy. HLA-B*58:01 positivity heightens SCAR risk, requiring alternative agents like febuxostat for gout management.

10. Identify the main gene used to guide initial warfarin dose due to sensitivity (reduced clearance).

    CYP2C9. CYP2C9 variants reduce warfarin metabolism, increasing sensitivity and bleeding risk, thus guiding lower initial dosing.

11. Which HLA allele is strongly associated with abacavir hypersensitivity reaction?

    HLA-B*57:01. HLA-B*57:01 variant predisposes individuals to severe immune-mediated hypersensitivity, making screening essential before abacavir initiation.

12. Which phenotype corresponds to two normal-function alleles for a metabolizing enzyme?

    Normal (extensive) metabolizer (NM/EM). Two functional alleles provide standard enzyme activity, aligning with population norms for drug metabolism.

13. Identify the CYP2C19 phenotype most associated with reduced clopidogrel activation and efficacy.

    Poor metabolizer (two loss-of-function alleles). Two loss-of-function CYP2C19 alleles diminish prodrug activation to its active metabolite, compromising antiplatelet efficacy.

14. Which FDA labeling category indicates testing is required or essential for safe/effective use?

    Companion diagnostic / testing required in labeling. FDA requires companion diagnostics when genetic testing is necessary to ensure drug safety and efficacy prior to prescribing.

15. What is the definition of a pharmacodynamic (PD) gene in pharmacogenomics?

    Gene affecting drug targets or pathways, altering response. Pharmacodynamic genes modulate drug-receptor interactions or signaling pathways, influencing therapeutic efficacy and potential side effects.

16. Which HLA allele is associated with allopurinol severe cutaneous adverse reactions (SCAR)?

    HLA-B*58:01. HLA-B*58:01 increases susceptibility to allopurinol-induced SCAR, particularly in high-risk ancestries, necessitating pre-treatment testing.

17. Which phenotype corresponds to two nonfunctional alleles for a metabolizing enzyme?

    Poor metabolizer (PM). Two loss-of-function alleles result in negligible enzyme activity, leading to drug accumulation and increased toxicity risk.

18. What is the thiopurine action for TPMT or NUDT15 poor metabolizers starting azathioprine?

    Use drastic dose reduction or alternative therapy. Poor metabolizer status in TPMT or NUDT15 leads to thiopurine toxicity, mandating significant dose reductions or alternative treatments.

19. What is the definition of a pharmacokinetic (PK) gene in pharmacogenomics?

    Gene affecting ADME, altering drug concentrations. Pharmacokinetic genes influence drug absorption, distribution, metabolism, and excretion, thereby impacting plasma levels and therapeutic outcomes.

20. What is the carbamazepine action if HLA-B*15:02 is positive and the patient is naïve?

    Avoid carbamazepine (and often oxcarbazepine) if possible. Positive HLA-B*15:02 in treatment-naïve patients elevates SJS/TEN risk, prompting selection of alternative antiepileptics.

21. Which organization provides widely used peer-reviewed PGx prescribing guidelines (CPIC)?

    Clinical Pharmacogenetics Implementation Consortium. CPIC develops evidence-based guidelines to translate pharmacogenetic test results into actionable prescribing recommendations.

22. What is the key CYP2C19-guided recommendation for clopidogrel in poor metabolizers?

    Avoid clopidogrel; use prasugrel or ticagrelor if appropriate. Poor metabolizers have impaired clopidogrel activation, increasing cardiovascular risk, so alternatives with different metabolism are preferred.

23. Which resource grades evidence and gives clinical action levels for gene–drug pairs (PharmGKB)?

    PharmGKB (Pharmacogenomics Knowledgebase). PharmGKB curates and annotates pharmacogenomic data, providing evidence levels to inform clinical decision-making for gene-drug interactions.

24. Which phenotype corresponds to one nonfunctional and one normal-function allele?

    Intermediate metabolizer (IM). This genotype yields partial enzyme activity, often requiring dose adjustments to balance efficacy and safety.

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