Pharmacogenetic PK/PD considerations MCQs With Answer

Pharmacogenetic PK/PD considerations MCQs With Answer

Introduction: This quiz collection focuses on pharmacogenetic principles that influence pharmacokinetics (PK) and pharmacodynamics (PD), an essential area for M.Pharm students preparing for clinical practice and therapeutic drug monitoring. Questions cover clinically important genes (CYPs, UGT, TPMT, SLCO, ABC transporters, HLA, NUDT15, NAT2, OCT1), their functional consequences, and how genetic variability guides dose selection, adverse-effect prevention and individualized TDM strategies. Case-relevant examples such as warfarin, clopidogrel, codeine, thiopurines, tacrolimus and statins deepen understanding of genotype–phenotype correlations, phenoconversion by drug interactions, and when genotype-informed decisions are recommended. These MCQs are designed to test applied knowledge and decision-making for real-world clinical pharmacokinetics.

Q1. What is the primary focus of pharmacogenetics in the context of PK/PD?

• Study of how drug formulations affect absorption kinetics
• Genetic variation in drug-metabolizing enzymes, transporters and targets that affects PK/PD
• Population-level drug resistance patterns unrelated to genetics
• Environmental factors controlling drug response

Correct Answer: Genetic variation in drug-metabolizing enzymes, transporters and targets that affects PK/PD

Q2. A patient who is an ultrarapid CYP2D6 metabolizer receives standard-dose codeine. What PK/PD outcome is most likely?

• Reduced conversion to morphine and therapeutic failure
• Increased conversion to morphine and risk of opioid toxicity
• No change because codeine is eliminated unchanged
• Lower plasma morphine due to increased renal clearance

Correct Answer: Increased conversion to morphine and risk of opioid toxicity

Q3. How does CYP2C19 poor metabolizer status affect clopidogrel therapy?

• Increased activation of clopidogrel and bleeding risk
• Decreased formation of active metabolite and reduced antiplatelet effect
• No effect because clopidogrel is not a prodrug
• Increased renal excretion of clopidogrel active metabolite

Correct Answer: Decreased formation of active metabolite and reduced antiplatelet effect

Q4. TPMT deficiency affects azathioprine and 6-mercaptopurine therapy by which mechanism?

• Faster renal elimination of thiopurines causing treatment failure
• Reduced conversion to active thioguanine nucleotides leading to lack of efficacy
• Accumulation of 6-thioguanine nucleotides causing severe myelosuppression
• Increased glucuronidation and decreased toxicity

Correct Answer: Accumulation of 6-thioguanine nucleotides causing severe myelosuppression

Q5. A loss-of-function SLCO1B1 variant (e.g., *5) most directly alters statin PK by which mechanism?

• Increasing hepatic uptake and reducing plasma exposure
• Reducing hepatic uptake and increasing systemic exposure, raising myopathy risk
• Enhancing renal clearance of statins
• Increasing intestinal absorption of statins

Correct Answer: Reducing hepatic uptake and increasing systemic exposure, raising myopathy risk

Q6. VKORC1 -1639G>A polymorphism impacts warfarin response primarily by:

• Altering warfarin renal clearance
• Changing target sensitivity resulting in lower dose requirements
• Increasing metabolism to inactive metabolites
• Increasing protein binding of warfarin

Correct Answer: Changing target sensitivity resulting in lower dose requirements

Q7. NUDT15 variants are clinically important because they predispose patients to which adverse effect with thiopurines?

• Hepatotoxicity without hematologic changes
• Intense early-onset myelosuppression, especially in East Asian patients
• Renal tubular acidosis
• Photosensitivity reactions

Correct Answer: Intense early-onset myelosuppression, especially in East Asian patients

Q8. UGT1A1*28 genotype increases toxicity of irinotecan by which pharmacokinetic mechanism?

• Increased renal clearance of SN-38
• Decreased glucuronidation of SN-38 resulting in higher active metabolite exposure and neutropenia
• Increased hepatic uptake of irinotecan reducing efficacy
• Enhanced conversion of irinotecan to inactive metabolites

Correct Answer: Decreased glucuronidation of SN-38 resulting in higher active metabolite exposure and neutropenia

Q9. ABCB1 (P-glycoprotein) loss-of-function variants can alter digoxin disposition by:

• Decreasing intestinal absorption of digoxin and lowering plasma levels
• Reducing efflux from tissues and increasing plasma and CNS concentrations
• Increasing hepatic metabolism of digoxin
• Promoting renal secretion of digoxin

Correct Answer: Reducing efflux from tissues and increasing plasma and CNS concentrations

Q10. How does CYP3A5 expression affect tacrolimus dosing requirements?

• Expressers require lower tacrolimus doses due to reduced clearance
• Expressers require higher tacrolimus doses due to increased metabolism
• No impact because tacrolimus is not metabolized by CYP3A5
• Expressers have prolonged half-life and need less frequent dosing

Correct Answer: Expressers require higher tacrolimus doses due to increased metabolism

Q11. What is phenoconversion in pharmacogenetics?

• Permanent change of genotype due to drug exposure
• A change in the drug-response phenotype caused by non-genetic factors such as concomitant inhibitors or inducers
• Conversion of prodrugs to active drugs by genotype-specific enzymes
• Mutation of transporter genes during therapy

Correct Answer: A change in the drug-response phenotype caused by non-genetic factors such as concomitant inhibitors or inducers

Q12. Which pre-therapy genetic test is recommended to prevent a life-threatening hypersensitivity reaction?

• CYP2D6 genotyping before codeine
• HLA-B*57:01 testing before abacavir therapy
• SLCO1B1 testing before low-dose aspirin
• NAT2 genotyping before isoniazid in all populations

Correct Answer: HLA-B*57:01 testing before abacavir therapy

Q13. A patient with SLCO1B1 loss-of-function allele begins simvastatin. Which monitoring or action is most appropriate?

• No change; SLCO1B1 has no effect on statins
• Consider lower simvastatin dose or alternative statin due to increased systemic exposure and myopathy risk
• Increase simvastatin dose to overcome reduced hepatic uptake
• Switch to fibrate therapy immediately

Correct Answer: Consider lower simvastatin dose or alternative statin due to increased systemic exposure and myopathy risk

Q14. CYP2C9*2 and *3 alleles affect warfarin therapy by:

• Increasing metabolic clearance requiring higher doses
• Reducing metabolic clearance leading to lower dose requirements and higher bleeding risk
• Increasing VKORC1 expression and causing resistance
• Altering warfarin absorption in the gut

Correct Answer: Reducing metabolic clearance leading to lower dose requirements and higher bleeding risk

Q15. NAT2 slow acetylator phenotype most commonly results in what change when treating tuberculosis with isoniazid?

• Reduced isoniazid plasma levels and treatment failure
• Higher isoniazid exposure with increased risk of hepatotoxicity and peripheral neuropathy
• Faster urinary excretion of isoniazid metabolites
• No clinically relevant effect on isoniazid PK/PD

Correct Answer: Higher isoniazid exposure with increased risk of hepatotoxicity and peripheral neuropathy

Q16. HLA-B*15:02 allele testing is particularly important before starting which drug in certain Asian populations?

• Phenytoin for heart failure
• Carbamazepine to reduce risk of Stevens–Johnson syndrome/toxic epidermal necrolysis
• Metformin to avoid lactic acidosis
• Warfarin for anticoagulation

Correct Answer: Carbamazepine to reduce risk of Stevens–Johnson syndrome/toxic epidermal necrolysis

Q17. Which transporter genotype most directly affects hepatic uptake and therapeutic response of metformin?

• SLCO1B1 variants
• SLC22A1 (OCT1) reduced-function variants that decrease hepatic uptake and may reduce efficacy
• ABCB1 variants increasing efflux from hepatocytes
• UGT1A1 promoter repeats

Correct Answer: SLC22A1 (OCT1) reduced-function variants that decrease hepatic uptake and may reduce efficacy

Q18. When is therapeutic drug monitoring (TDM) most useful in the context of pharmacogenetic variability?

• For drugs with wide therapeutic indices and no genetic influence
• For drugs with narrow therapeutic index, large genetic effect on PK, and available concentration–response relationships (e.g., tacrolimus)
• Only when genotyping is unavailable
• Never; genotyping alone is always sufficient

Correct Answer: For drugs with narrow therapeutic index, large genetic effect on PK, and available concentration–response relationships (e.g., tacrolimus)

Q19. In star allele nomenclature (e.g., CYP2D6*4), what does the “*4” represent?

• An expression level measured in phenotype tests
• A specific haplotype or allele with defined sequence variants and functional consequence
• The number of copies of the gene in the genome
• The enzyme activity measured in nmol/min/mg

Correct Answer: A specific haplotype or allele with defined sequence variants and functional consequence

Q20. The UGT1A1*28 polymorphism mechanism is best described as:

• A missense mutation causing complete loss of enzyme activity
• An insertion of additional TA repeats in the promoter that reduces transcription and glucuronidation capacity
• A frameshift mutation leading to truncated protein with increased activity
• Enhanced UGT1A1 expression resulting in faster drug clearance

Correct Answer: An insertion of additional TA repeats in the promoter that reduces transcription and glucuronidation capacity

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