Medical Pharmacology Question Bank

Chapter 1: General Pharmacology — Module 5: Drug Development and Regulation
Tier: Tier 3 — Clinical Vignettes

1. A 38-year-old woman of Ethiopian descent undergoes elective cholecystectomy. Postoperatively she is prescribed codeine 30 mg every four hours for pain. On postoperative day one, the nursing staff finds her unresponsive with a respiratory rate of 4 breaths per minute, pinpoint pupils, and oxygen saturation of 78% on room air. She had received only two doses of codeine. Her husband mentions she had been breastfeeding their three-month-old infant, who was brought in separately in respiratory distress. CYP2D6 genotyping later reveals she carries three functional CYP2D6 copies. Which of the following best explains the pharmacogenomic mechanism of both the mother's toxicity and the infant's respiratory distress, and identifies the prescribing error that should have been anticipated?

A) The mother is a CYP2D6 poor metabolizer who cannot convert codeine to morphine — her unresponsiveness results from direct codeine toxicity at mu-opioid receptors at supratherapeutic plasma concentrations; the infant's distress results from placental transfer during the immediate postpartum period
B) The mother is a CYP2D6 ultrarapid metabolizer carrying three functional gene copies, producing markedly elevated CYP2D6 enzyme activity; codeine is rapidly and extensively converted to morphine, generating supratherapeutic systemic morphine concentrations causing respiratory depression in the mother at standard codeine doses; morphine is transferred to the breastfeeding infant through breast milk, producing neonatal opioid toxicity and respiratory depression; the prescribing error was failure to recognize that Ethiopian descent is associated with high CYP2D6 UM prevalence and that codeine is contraindicated in breastfeeding mothers regardless of metabolizer status, and is particularly dangerous in UM individuals
C) The mother has a CYP2D6 intermediate metabolizer phenotype that reduces codeine conversion to morphine by 50%; the accumulated codeine itself (not morphine) produces respiratory depression through direct mu-opioid receptor agonism; the infant's distress results from codeine transfer through breast milk acting directly on neonatal mu-opioid receptors
D) The toxicity results from a drug-drug interaction between codeine and the general anesthetic used intraoperatively — volatile anesthetics induce CYP2D6, converting an extensive metabolizer to a functional ultrarapid metabolizer phenotype transiently, and this induction persists for 48–72 hours postoperatively
E) The mother is a CYP2D6 ultrarapid metabolizer, but the mechanism of neonatal toxicity is direct codeine passage through breast milk acting on immature neonatal mu-opioid receptors — morphine itself is too large a molecule to cross the neonatal blood-brain barrier and cannot produce central respiratory depression in infants under six months of age

ANSWER: B

Rationale:

This case is drawn directly from the tragic real-world events that prompted the FDA and Health Canada to issue contraindications and black box warnings for codeine in breastfeeding mothers and children under 12. The pharmacogenomic mechanism is precisely characterized: the mother carries three functional CYP2D6 alleles, conferring an ultrarapid metabolizer phenotype with markedly supranormal CYP2D6 enzymatic activity. CYP2D6 ultrarapid metabolizer prevalence is highest in populations of North African and East African descent — in Ethiopian populations, UM prevalence approaches 29%, making it the most prevalent metabolizer phenotype in this population group. In this UM mother, codeine undergoes rapid and extensive O-demethylation to morphine — generating systemic morphine concentrations several fold higher than expected in an extensive metabolizer at the same codeine dose. The mother develops opioid toxicity (respiratory depression, sedation, miosis) after only two standard doses. Morphine generated in the mother's circulation is actively transferred into breast milk — morphine breast milk concentrations in UM mothers have been measured at levels 1.5–2.6 mg/L (compared to <0.5 mg/L in EM mothers at equivalent doses). The three-month-old infant, whose hepatic morphine glucuronidation capacity is limited, blood-brain barrier is more permeable, and respiratory centers are more sensitive to opioid-mediated depression, receives a pharmacologically significant morphine dose through breast milk and develops neonatal opioid toxicity. The prescribing error was multi-layered: failure to elicit ancestry (Ethiopian descent carrying high UM prevalence), failure to recognize that breastfeeding is an absolute contraindication to codeine regardless of metabolizer status (per current guidelines), and failure to use a safer postoperative analgesic (acetaminophen, NSAIDs, regional analgesia). Option A describes a PM phenotype and reverses the mechanism — PMs experience analgesic failure, not toxicity. Option C describes an IM phenotype with an incorrect mechanism — codeine itself has very low intrinsic mu-opioid receptor affinity and does not cause significant respiratory depression as the parent compound at standard doses. Option D is incorrect — volatile anesthetics do not meaningfully induce CYP2D6; enzyme induction via PXR/CAR nuclear receptors does not apply to CYP2D6. Option E is incorrect — morphine readily crosses the neonatal blood-brain barrier; its molecular weight (285 g/mol) and moderate lipophilicity allow CNS penetration in neonates, whose blood-brain barrier is more permeable than that of adults.

2. A 58-year-old man with acute myeloid leukemia (AML) is initiated on 6-mercaptopurine (6-MP) as part of a maintenance protocol. Prior to initiation, TPMT genotyping reveals he is a TPMT intermediate metabolizer (one functional and one loss-of-function allele, activity score 1.0). NUDT15 genotyping reveals he is a NUDT15 normal metabolizer (two functional alleles). On day 14 of standard-dose 6-MP, his complete blood count shows an absolute neutrophil count of 0.08 × 10/L, hemoglobin 6.2 g/dL, and platelet count 18 × 10/L — severe pancytopenia. Which of the following best explains the pharmacogenomic basis of his toxicity and identifies the most appropriate dose adjustment strategy going forward?

A) NUDT15 normal metabolizer status is the primary driver of 6-MP myelosuppression — his TPMT intermediate metabolizer status is pharmacogenomically irrelevant because NUDT15 is the dominant enzyme in 6-TGN metabolism; the 6-MP dose should be reduced by 90% and NUDT15 genotyping repeated
B) TPMT intermediate metabolizer status (one functional allele) produces partial reduction in thiopurine inactivation, resulting in 6-TGN accumulation approximately 1.5–2 fold above EM levels at standard doses; while IM patients tolerate standard doses less well than EM patients, the degree of myelosuppression observed here (severe pancytopenia) suggests that additional contributing factors may be present — including disease-related bone marrow reserve depletion from AML, concurrent medications, or nutritional deficiencies; CPIC recommends 30–70% dose reduction for TPMT IMs initiating thiopurines, with careful monitoring; going forward, 6-MP should be restarted at a substantially reduced dose (approximately 30–50% of standard) with frequent CBC monitoring
C) The myelosuppression confirms that the patient is actually a TPMT poor metabolizer despite his genotyping result — the discordance between genotype and phenotype indicates laboratory error; genotyping should be repeated and 6-MP held until a PM genotype is confirmed
D) TPMT intermediate metabolizer status has no clinical pharmacogenomic significance for 6-MP dosing — only TPMT poor metabolizers require dose reduction; the pancytopenia is attributable entirely to AML disease progression and is unrelated to 6-MP pharmacogenomics
E) The appropriate response to severe 6-MP myelosuppression in a TPMT intermediate metabolizer is to switch to azathioprine, which bypasses TPMT-mediated metabolism entirely and can be dosed at standard levels without pharmacogenomic consideration

ANSWER: B

Rationale:

This case illustrates the nuanced clinical application of TPMT intermediate metabolizer pharmacogenomics in the context of oncological thiopurine therapy. TPMT catalyzes S-methylation of thiopurines and their metabolites, inactivating them and diverting substrate away from the 6-TGN pathway. TPMT intermediate metabolizers (one functional allele, activity score approximately 1.0) have partial reduction in TPMT enzyme activity — approximately 50% of wild-type (EM) activity. At standard 6-MP doses, TPMT IMs generate 6-TGN concentrations approximately 1.5–2 fold higher than EMs, resulting in greater myelosuppressive effect. CPIC guidelines (Level A evidence) recommend that TPMT IMs initiating thiopurines receive a 30–70% dose reduction from the standard starting dose, with individual titration guided by CBC and red blood cell 6-TGN concentration monitoring. The severe pancytopenia observed on day 14 — ANC 0.08, Hgb 6.2, platelets 18 — represents profound bone marrow suppression. While the TPMT IM pharmacogenomic status predicts vulnerability to 6-TGN accumulation, the severity of this toxicity warrants consideration of additional contributing factors: AML itself disrupts bone marrow reserve, reducing tolerance for cytotoxic therapy; concurrent medications (other myelosuppressive agents, TMP-SMX for Pneumocystis prophylaxis — which through DHFR inhibition adds to myelosuppression); and nutritional status. Management: hold 6-MP until CBC recovers (ANC >1.0, platelets >75); restart at 30–50% of the previous dose with weekly CBC monitoring for at least 4 weeks; measure red blood cell 6-TGN concentrations to guide dose titration; assess and address contributing factors. Option A is incorrect — NUDT15 IM and PM status do predict 6-TGN toxicity risk, but in this patient NUDT15 normal metabolizer status means NUDT15 variation is not contributing; TPMT IM status is the relevant pharmacogenomic driver here. Option C is incorrect — the discordance between expected IM toxicity and the observed severe pancytopenia does not automatically indicate genotyping error; additional clinical factors (disease state, concurrent therapies) must be considered before attributing all toxicity to genotype mislabeling. Option D is incorrect — TPMT IM status is clinically significant and CPIC-actionable; dose reduction is recommended for IM patients, not only for PMs. Option E is incorrect — azathioprine is a prodrug converted to 6-MP as its first metabolic step; it is equally subject to TPMT-mediated metabolism and carries identical myelosuppression risk in TPMT IMs and PMs; it does not bypass TPMT metabolism.

3. A 29-year-old woman with HIV infection, currently virologically suppressed on a regimen containing abacavir-lamivudine-dolutegravir, presents to her infectious disease clinic for routine review. She discloses she has been prescribed carbamazepine by a neurologist for newly diagnosed epilepsy. She is of Thai descent and was found to be HLA-B*5701 negative (confirmed prior to abacavir initiation three years ago). The infectious disease physician immediately expresses concern about the carbamazepine prescription. Which of the following best explains the physician's concern, and what pharmacogenomic evaluation is now required?

A) The physician is concerned that carbamazepine will inhibit CYP3A4, reducing dolutegravir metabolism and increasing its plasma concentrations to toxic levels — the required evaluation is therapeutic drug monitoring of dolutegravir, not pharmacogenomic testing
B) The physician is concerned that HLA-B*5701 negativity does not protect against carbamazepine-induced hypersensitivity — carbamazepine-induced SJS/TEN in Thai patients is associated with HLA-B*1502, a completely different allele from HLA-B*5701; this patient's prior negative HLA-B*5701 result provides no information about her HLA-B*1502 status; given her Thai descent and the high prevalence of HLA-B*1502 in Thai populations (approximately 10–15%), HLA-B*1502 genotyping must be performed before carbamazepine is initiated; if HLA-B*1502 positive, carbamazepine is contraindicated and an alternative antiepileptic not associated with HLA-B*1502 SCAR (such as levetiracetam or valproate) should be used
C) The physician is concerned that carbamazepine, as a CYP3A4 inducer, will reduce abacavir plasma concentrations through induction of intestinal CYP3A4 — abacavir is a CYP3A4 substrate and its reduced bioavailability will compromise HIV viral suppression; the required evaluation is HLA-B*5701 repeat testing to confirm ongoing abacavir safety
D) The physician is concerned that HLA-B*1502 and HLA-B*5701 are in complete linkage disequilibrium in Thai populations — since the patient tested negative for HLA-B*5701, she is automatically negative for HLA-B*1502 and carbamazepine can be safely prescribed without additional genotyping
E) The physician's concern is entirely pharmacokinetic — carbamazepine induces its own metabolism (autoinduction via CYP3A4) and will also induce dolutegravir metabolism, reducing viral suppression; the required evaluation is dolutegravir plasma level monitoring and possible dose doubling, with no pharmacogenomic testing needed

ANSWER: B

Rationale:

This case elegantly illustrates a critical pharmacogenomic clinical pitfall: the assumption that a negative result for one HLA allele provides information about a different, unrelated HLA allele. HLA-B*5701 and HLA-B*1502 are entirely distinct HLA-B alleles located on different haplotypes — they are not in linkage disequilibrium with each other, they are detected by different molecular assays, and they are associated with different drugs and adverse reactions. The patient's prior HLA-B*5701 testing (performed for abacavir safety screening three years ago) established only that she does not carry HLA-B*5701 — it provides absolutely no information about her HLA-B*1502 carrier status. In Thai populations, HLA-B*1502 prevalence is approximately 10–15% — one of the highest prevalences globally — making the prior probability that this patient carries HLA-B*1502 clinically non-negligible. HLA-B*1502 is strongly associated with carbamazepine-induced SJS and TEN in Thai, Han Chinese, and Southeast Asian populations (odds ratio >1000 for SJS/TEN in carriers vs non-carriers). Both the FDA (mandated for patients of Asian ancestry) and CPIC (Level A evidence) require HLA-B*1502 genotyping before carbamazepine initiation in patients of relevant Asian ancestry. If this patient is HLA-B*1502 positive, carbamazepine is contraindicated — alternative antiepileptic drugs without HLA-B*1502 SCAR associations (levetiracetam, valproate, lamotrigine — noting that cross-reactivity evidence for lamotrigine with HLA-B*1502 in some studies warrants consideration) should be used. Additionally, carbamazepine is a potent CYP3A4 inducer that would reduce dolutegravir plasma concentrations through induction of its metabolism — a significant pharmacokinetic drug interaction warranting antiretroviral regimen review, but this pharmacokinetic concern is separate from and does not supersede the pharmacogenomic safety evaluation. Option A identifies the pharmacokinetic concern (carbamazepine-dolutegravir CYP3A4 induction interaction) but misses the primary and more immediately urgent pharmacogenomic safety concern. Option C incorrectly states that abacavir is a CYP3A4 substrate — abacavir is primarily metabolized by alcohol dehydrogenase and glucuronyl transferase, not by CYP3A4; repeat HLA-B*5701 testing is not indicated as the genotype does not change. Option D is critically incorrect — HLA-B*1502 and HLA-B*5701 are not in linkage disequilibrium; a negative HLA-B*5701 result provides no information about HLA-B*1502 status. Option E identifies a real pharmacokinetic concern (carbamazepine CYP3A4 autoinduction reducing dolutegravir) but is incomplete and incorrect in stating no pharmacogenomic testing is needed — HLA-B*1502 testing is the immediate priority.

4. A 67-year-old man with type 2 diabetes, hypertension, and newly diagnosed non-small cell lung cancer (NSCLC) is being evaluated for systemic therapy. Molecular profiling of his tumor biopsy reveals an EGFR exon 19 deletion. His oncologist proposes erlotinib — a first-generation EGFR tyrosine kinase inhibitor (TKI). A clinical pharmacist notes that the patient is also on omeprazole for gastroesophageal reflux. Germline CYP3A4 genotyping returns as extensive metabolizer (wild-type). Which of the following best integrates the relevant pharmacogenomic, pharmacokinetic, and molecular pathology considerations for this patient's therapy?

A) The EGFR exon 19 deletion is a somatic tumor mutation that predicts erlotinib sensitivity — this is an example of tumor pharmacogenomics (somatic mutation-guided therapy) rather than germline pharmacogenomics; erlotinib is an appropriate targeted therapy; however, omeprazole raises gastric pH and reduces erlotinib absorption (erlotinib solubility is pH-dependent), representing a pharmacokinetic drug interaction that may reduce erlotinib plasma concentrations and efficacy — omeprazole should ideally be discontinued or replaced with an H2 blocker taken at a separated time interval; germline CYP3A4 extensive metabolizer status does not require dose adjustment
B) The EGFR exon 19 deletion is a germline pharmacogenomic variant that predicts erlotinib sensitivity in all tissues — germline EGFR genotyping should be performed on peripheral blood rather than tumor biopsy to confirm the mutation in non-tumor cells before initiating targeted therapy
C) Erlotinib's efficacy is determined exclusively by germline CYP3A4 genotype — CYP3A4 extensive metabolizers are the ideal candidates for erlotinib as they maintain therapeutic plasma concentrations; tumor EGFR mutation status is a secondary consideration that does not affect erlotinib prescribing decisions
D) Omeprazole inhibits CYP3A4 and will markedly increase erlotinib plasma concentrations, requiring a 50% erlotinib dose reduction; the EGFR exon 19 deletion has no predictive pharmacogenomic value and erlotinib should not be selected on the basis of tumor molecular profiling alone
E) The patient's germline CYP3A4 extensive metabolizer status combined with the EGFR exon 19 somatic deletion predicts that erlotinib will be rapidly metabolized to an inactive form before it can reach the tumor — osimertinib should be used instead because it is not metabolized by CYP3A4

ANSWER: A

Rationale:

This case integrates three distinct pharmacological domains that are frequently conflated but must be clearly distinguished: somatic tumor pharmacogenomics (molecular pathology guiding targeted therapy selection), germline pharmacogenomics (inherited variant metabolism predicting drug handling), and conventional pharmacokinetics (drug-drug interactions affecting drug exposure). The EGFR exon 19 deletion is a somatic mutation — acquired in the tumor during carcinogenesis, present in tumor cells but not in germline. This mutation constitutively activates the EGFR tyrosine kinase domain, rendering the kinase highly sensitive to competitive ATP-site inhibition by erlotinib. EGFR exon 19 deletions predict erlotinib (and other first/second-generation EGFR TKI) sensitivity with objective response rates of 60–70% and significantly prolonged progression-free survival compared to cytotoxic chemotherapy. This is a canonical example of somatic tumor pharmacogenomics — the tumor's genetic profile (not the patient's germline) determines drug sensitivity. Germline CYP3A4 extensive metabolizer status is relevant to erlotinib pharmacokinetics (erlotinib is a CYP3A4 substrate) but does not modify the therapeutic decision in this patient — wild-type CYP3A4 EM status represents standard metabolism requiring no dose adjustment. The omeprazole interaction is a pharmacokinetic concern: erlotinib's solubility and absorption are strongly pH-dependent — it is a weak base (pKa approximately 5.4) that requires acidic gastric pH for dissolution and absorption. Omeprazole-mediated gastric acid suppression raises gastric pH, reducing erlotinib solubility and absorption, and pharmacokinetic studies demonstrate that omeprazole reduces erlotinib AUC by approximately 46%. This clinically meaningful reduction in erlotinib exposure may reduce antitumor efficacy. Management: discontinue omeprazole if clinically feasible; if acid suppression is necessary, an H2-receptor antagonist (ranitidine — now unavailable in most markets due to NDMA concerns; famotidine) taken at least 10 hours before and 2 hours after erlotinib can minimize the interaction; antacids taken at separated time intervals are an additional option. Option B is incorrect — the EGFR exon 19 deletion is a somatic tumor mutation, not a germline pharmacogenomic variant; germline EGFR testing is irrelevant to erlotinib prescribing decisions. Option C is incorrect — tumor EGFR mutation status is the primary determinant of erlotinib selection; germline CYP3A4 status is a secondary pharmacokinetic consideration. Option D is incorrect — omeprazole reduces erlotinib absorption through a pH-dependent solubility mechanism, not through CYP3A4 inhibition; omeprazole has minimal CYP3A4 inhibitory activity at clinical doses. Option E is incorrect — CYP3A4 extensive metabolizer status does not produce clinically insufficient erlotinib exposure at standard doses; while CYP3A4 inducers may reduce erlotinib exposure significantly, EM status does not; osimertinib selection would be based on resistance mutation profile (T790M) or as first-line per current guidelines, not on CYP3A4 genotype. This Web-based pharmacology and disease-based integrated teaching site is based on reference materials, that are believed reliable and consistent with standards accepted at the time of development. Possibility of error and on-going research and development in medical sciences do not allow assurance that the information contained herein is in every respect accurate or complete. Users should confirm the information contained herein with other sources. This site should only be considered as a teaching aid for undergraduate and graduate biomedical education and is intended only as a teaching site. Information contained here should not be used for patient management and should not be used as a substitute for consultation with practicing medical professionals. Users of this website should check the product information sheet included in the package of any drug they plan to administer to be certain that the information contained in this site is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. Medical or other information thus obtained should not be used as a substitute for consultation with practicing medical or scientific or other professionals.