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Pharmacogenomics

Chapter 72 | Part 3: Pharmacology · Part 3 – Pharmacology · Chapter 72

Key Clinical Points

  1. Pharmacogenomics studies how genetic variation (metabolism, transport, target) modulates drug response and adverse drug reactions (ADRs).
  2. Phenotypes include Poor Metabolizers (PM), Extensive Metabolizers (EM), and Ultra-rapid Metabolizers (UM), which significantly affect steady-state concentrations and time to reach steady state.
  3. CYP2D6 variants impact codeine (risk of respiratory depression in UMs), beta-blockers (bradycardia risk in PMs), and tamoxifen efficacy.
  4. CYP2C19 variants influence clopidogrel activation (reduced in PMs) and omeprazole response (higher cure rates in PMs).
  5. CYP2C9 and VKORC1 variants account for up to 50% of the variability in warfarin dose requirements.
  6. HLA-B57:01 testing is mandatory before abacavir to prevent SJS/TEN; HLA-B15:02 is recommended before carbamazepine in high-risk populations to prevent SJS/TEN.
  7. TPMT and NUDT15 variants require dose reductions for thiopurines (azathioprine, 6-MP) to prevent fatal myelosuppression.
  8. DPYD variants increase the risk of severe toxicity with 5-fluorouracil (5-FU), capecitabine, and tegafur.
  9. UGT1A1 variants (associated with Gilbert's syndrome) increase risk of irinotecan-induced diarrhea and bone marrow depression; atazanavir can also increase bilirubin in these patients.
  10. Preemptive pharmacogenetic screening allows for integration into Electronic Health Records (EHR) and real-time Clinical Decision Support (CDS).
  11. FDA package inserts now incorporate pharmacogenetic data, including warnings for codeine in children.

DEFINITION & OVERVIEW

• Pharmacogenomics: The study of how genetic variation influences drug response. • Scope: Extends from pharmacogenetics (single genetic variants in individual subjects) to pharmacogenomics (multiple genetic variants across populations). • Clinical Goals: ◦ Improve the use of current drugs. ◦ Avoid drug use in those at increased risk for adverse drug reactions (ADRs). ◦ Guide development of new drugs. ◦ Use as a lens to understand mechanisms of diseases. • Evidence Base: ◦ Requires replication before acceptance as valid. ◦ Uses both candidate gene and genome-wide association studies (GWA). ◦ GWA identified HLA variants associated with severe skin rashes (carbamazepine) and hepatotoxicity (flucloxacillin). ◦ GWA of simvastatin-associated myopathy identified a noncoding SNP in SLCO1B1 (encoding OATP1B1), which accounts for 60% of myopathy risk. ◦ African-American subjects often require higher warfarin doses due to variations in CYP2C9 and VKORC1.

Principles of Genetic Variation

• Genetic Basis: ◦ Single Nucleotide Polymorphism (SNP): The most common type of genetic variant. ◦ Nonsynonymous SNPs: Alter primary amino acid sequence; common in pharmacogenes. ◦ Structural Variants: Small insertions and deletions can alter protein function or lead to functionally important splice variation. ◦ Other Mechanisms: ◦ Synonymous coding region variants (alter translation/folding). ◦ Variation in pharmacogene promoters. ◦ Copy number variation (gene deletion or multiple functional copies).

EPIDEMIOLOGY

• Ancestry-Specific Risks: ◦ CYP3A5: Most Europeans and Asians carry a polymorphism disrupting splicing (low activity); Africans often lack this, leading to faster clearance of drugs like tacrolimus. ◦ CYP2D6: 5–10% of European/African populations are PMs; few Asians are PMs. ◦ CYP2C19: PM phenotype is common (20%) among Asians, rarer (2–3%) in other populations, and very high (>50%) in Oceania. ◦ NAT2: Slow acetylators comprise ~50% of European/African populations; less common in East Asians. ◦ UGT1A1: Common promoter polymorphism leads to Gilbert's syndrome; associated with irinotecan toxicity and atazanavir-induced hyperbilirubinemia. ◦ Warfarin: African-Americans often require higher doses due to CYP2C9 and VKORC1 variations.

ETIOLOGY & PATHOPHYYSOLOGY

• Metabolic Phenotypes: ◦ Poor Metabolizers (PM): Individuals with two alleles encoding nonfunctional protein → slower elimination, higher steady-state concentrations, and longer time to reach steady state. ◦ Intermediate Metabolizers: Individuals with one functional allele or multiple reduced-function alleles. ◦ Ultra-rapid Metabolizers (UM): High enzymatic activity (often due to SNPs or gene duplication) → lower steady-state concentration and shorter time to steady state. ◦ Phenocopying: EM individuals receiving specific inhibitors may exhibit a PM phenotype.

Pharmacokinetic (PK) Variants

• CYP3A Family: ◦ CYP3A4: High variability (up to an order of magnitude); likely due to regulatory region variations. ◦ CYP3A5: Splicing mutations in Europeans/Asians lead to lower activity; higher activity in Africans. ◦ CYP2D6: Second most common drug-metabolizing enzyme. PMs have slower elimination and higher steady-state concentrations. ◦ CYP2C19: Impacts clopidogrel (reduced activation in PMs) and omeprazole (higher cure rates in PMs). ◦ CYP2C9: Loss-of-function alleles linked to phenytoin complications, glipizide hypoglycemia, and reduced warfarin requirements. ◦ DPYD: Loss-of-function leads to 5-FU, capecitabine, and tegafur toxicity; intermediate metabolizers require dose reductions. ◦ TPMT & NUDT15: TPMT deficiency → fatal pancytopenia with azathioprine or 6-MP. NUDT15 variants also increase myelosuppression risk. ◦ UGT1A1: Reduced transcription leads to higher irinotecan toxicity and atazanavir-induced hyperbilirubinemia. ◦ Transporter Variants: ◦ SLCO1B1: Linked to simvastatin myopathy (60% of risk). ◦ MDR1: Linked to digoxin toxicity. ◦ MATE1/MATE2: Modulate metformin's glucose-lowering activity.

Pharmacodynamic (PD) Variants

• VKORC1: Promoter variants (common in Asians) reduce transcription → lower warfarin dose required. ◦ β-adrenergic receptor: Polymorphisms linked to asthma/CHF drug responses and heart rate/blood pressure changes. ◦ G6PD: Deficiency (African, Mediterranean, South Asian) → hemolysis with primaquine or rasburicase. ◦ RYR1: Mutations cause malignant hyperthermia when exposed to general anesthetics. ◦ QT Prolongation: Certain antiarrhythmics can unmask subclinical long QT syndrome.

CLINICAL FEATURES

• Codeine & CYP2D6: ◦ Codeine is biotransformed to morphine by CYP2D6. ◦ PMs: Blunted effect. ◦ UMs: Exaggerated effect → risk of respiratory depression (especially in children). ◦ FDA Action: Updated package insert for codeine in children. • Beta-Blockers & CYP2D6: ◦ PMs: Greater signs of beta blockade (bradycardia, bronchospasm) with metoprolol, carvedilol, timolol, and propafenefone. • Antidepressants: UMs may require higher doses of nortriptyline. • Tamoxifen: Efficacy linked to CYP2D6-mediated conversion to active metabolites. • Isoniazid & Procainamide: Slow acetylators have increased risk of hepatitis (isoniazid) and drug-induced lupus (procainamide). • SJS/TEN: ◦ HLA-B57:01: Risk for abacavir (SJS/TEN) and flucloxacillin (hepatotoxicity). ◦ HLA-B15:02: Risk for carbamazepine (SJS/TEN) in high-risk populations.

DIAGNOSTIC APPROACH

  1. Select Genotyping Method: • Use SNP assays for common variants. • Use Sequencing for highly polymorphic regions (e.g., HLA locus).
  2. Identify Specific Variants: • Identify SNPs in SLCO1B1 (simvastatin), CYP2C9/VKORC1 (warfarin), or DPYD (5-FU).
  3. Determine Phenotype: • Categorize as PM, EM, or UM based on allele count and function. • Determine if 'phenocopying' is occurring due to drug-drug interactions.

MANAGEMENT & TREATMENT

  1. Evaluate Clinical Impact: • Assess magnitude of genetic effect. • Evaluate strength of evidence (e.g., GWA vs. clinical trials). • Consider cost vs. expected benefit.
  2. Select Implementation Strategy: • Point-of-Care Approach: ◦ Order variant-specific assays at time of prescription. ◦ Rapid results (1–2 hours) used to guide immediate therapy. • Preemptive Approach: ◦ Test for multiple variants prior to any prescription. ◦ Integrate data into Electronic Health Records (EHR). ◦ Link to real-time Clinical Decision Support (CDS) to alert providers.

Drug-Specific Management

• Codeine: Avoid in children; use caution in CYP2D6 UMs. ◦ Warfarin: Adjust dose based on CYP2C9 and VKORC1 status (up to 50% of variance). ◦ Thiopurines: Reduce dose for patients with TPMT or NUDT15 variants. ◦ 5-Fluorouracil/Capecitabine: Dose reduction recommended for DPYD intermediate metabolizers. ◦ Abacavir: Test for HLA-B57:01 before use. ◦ Carbamazepine: Test for HLA-B15:02 in high-risk populations.

KEY PEARLS & CLINICAL TRAPS

• Rule of Thumb: PMs have higher steady-state concentrations and longer half-lives; UMs have lower steady-state concentrations and shorter half-lives. ◦ Clinical Trap: HLA alleles are necessary but not sufficient for SJS/TEN; presence of the allele indicates risk, not certainty of reaction. ◦ Critical Thresholds: CYP2C19 PM is common (20%) in Asians; CYP2D6 PM is 5–10% in European/African populations. ◦ Warfarin Logic: 50% of dose variability is driven by CYP2C9 and VKORC1. ◦ Irinotecan Risk: UGT1A1 variants (Gilbert's) increase risk of diarrhea and bone marrow depression.