Improving Patient Care with Pharmacogenomic Testing

PATHCHAT Edition No. 84
Published: 2023
Please contact your local Ampath pathologist for more information.

Authors:

• Dr. Janin Alant
• Karmishtha Hutheram

Key Messages

✅ What is Pharmacogenomic Testing (PGT)?

• Investigates how an individual’s genetic makeup influences their response to medication.
• Small genetic variations within pharmacogenes (e.g., cytochrome P450 enzymes) affect drug absorption, metabolism, and excretion.
• Pre-emptive PGT can reduce adverse drug reactions and improve treatment compliance.

✅ Why is PGT Important?

• Improves personalised prescribing and dosing.
• Reduces hospitalisations due to drug-related adverse effects.
• PGT is now cost-effective and widely accessible through larger panel-based testing like PGx120.

✅ Sample & Turnaround Time

• Sample Type: Buccal swab or peripheral blood (EDTA tube).
• Mnemonic: PHARMA.
• Turnaround Time: 10 working days from sample receipt at Ampath’s NRL Genetics Laboratory.

📌 Pharmacogenomic testing enhances precision medicine by tailoring drug therapy to an individual’s genetic profile.

How is Pharmacogenomic Evidence Reviewed and Curated?

✅ Reliable Sources for PGT Guidelines

• Clinical Pharmacogenomics Implementation Consortium (CPIC)
  • Publishes updated and peer-reviewed guidelines on drug-gene interactions.
  • Recommends genotype-based dosing adjustments.
• Pharmacogenomics Knowledge Base (PharmGKB)
  • Database for drug-gene interactions.
• Dutch Pharmacogenetics Working Group (DPWG)
  • Provides genotype-guided prescribing recommendations.

📌 PGT recommendations are based on international guidelines that are continuously updated as new evidence emerges.

Types of Pharmacogenomic Testing

✅ Single Gene Testing

• Example: TPMT genotyping before prescribing thiopurines.
• Used when a specific drug-gene interaction is suspected.

✅ Panel-Based Testing (PGx120)

• Assesses multiple drug-gene interactions in a single test.
• Detects ~120 genetic changes across 36 known pharmacogenes.
• Provides genotype-based dosing algorithms for over 150 medications.

📌 Panel-based PGT is now more affordable and widely available, improving patient outcomes.

Examples of PGT in Clinical Practice

1. Codeine Metabolism and CYP2D6 Genotyping

✅ How CYP2D6 Affects Codeine Response

• Codeine is a prodrug that is metabolised into morphine by CYP2D6.
• Genetic variations in CYP2D6 alter this conversion:
  • Ultra-rapid metabolisers: Convert too much codeine to morphine, leading to overdose risks.
  • Poor metabolisers: Convert very little codeine to morphine, leading to inadequate pain relief.

✅ Clinical Implications of PGT for Codeine

• Ultra-rapid metabolisers should avoid codeine due to toxicity risks.
• Poor metabolisers should be prescribed an alternative analgesic.
• PGT helps clinicians select safer and more effective pain management options.

📌 CYP2D6 testing prevents life-threatening complications from codeine and tramadol use.

2. Warfarin Dosing and CYP2C9/VKORC1 Genotyping

✅ Warfarin Sensitivity and Genetic Variants

• Warfarin is metabolised by CYP2C9 and targets VKORC1.
• Patients with CYP2C9 variants require lower warfarin doses to avoid bleeding risks.
• VKORC1 variants also influence warfarin sensitivity and dosing requirements.

✅ Clinical Impact of Warfarin PGT

• Reduces time required to achieve stable anticoagulation.
• Minimises the risk of warfarin-related bleeding events.
• Improves patient adherence and reduces emergency hospital visits.

📌 PGT-guided warfarin dosing ensures safer and more effective anticoagulation therapy.

3. Statins and SLCO1B1 Variants

✅ How SLCO1B1 Affects Statin Therapy

• SLCO1B1 encodes a liver transporter responsible for statin uptake.
• Certain genetic variants reduce SLCO1B1 function, leading to:
  • Increased risk of statin-induced muscle pain (SAMS).
  • Potential for severe complications like rhabdomyolysis.

✅ Clinical Benefits of SLCO1B1 Genotyping

• Identifies patients at risk for statin intolerance.
• Guides alternative statin selection or dose adjustments.
• Improves adherence to lipid-lowering therapy.

📌 SLCO1B1 testing helps prevent unnecessary discontinuation of statins due to side effects.

4. Antidepressants and CYP2C19/CYP2D6 Genotyping

✅ How CYP2C19 & CYP2D6 Affect SSRI Response

• CYP2C19 and CYP2D6 influence the metabolism of selective serotonin reuptake inhibitors (SSRIs), such as:
  • Citalopram.
  • Escitalopram.
  • Fluoxetine.

✅ Clinical Benefits of Genotyping for Antidepressants

• Ultra-rapid metabolisers clear the drug too quickly, leading to treatment failure.
• Poor metabolisers experience excessive drug accumulation, increasing the risk of side effects.
• PGT allows for dose adjustments or alternative drug selection based on metabolism rate.

📌 PGT enhances psychiatric medication effectiveness while reducing side effects and treatment resistance.

5. Proton Pump Inhibitors (PPIs) and CYP2C19 Genotyping

✅ CYP2C19 and PPI Response

• CYP2C19 influences the metabolism of common PPIs, such as:
  • Omeprazole.
  • Lansoprazole.
  • Pantoprazole.

✅ Clinical Benefits of PGT for PPIs

• Ultra-rapid metabolisers clear PPIs too quickly, leading to treatment failure.
• Poor metabolisers accumulate PPIs, increasing the risk of toxicity.
• PGT-guided dosing improves treatment efficacy for acid reflux and Helicobacter pylori infections.

📌 PGT ensures optimal dosing of PPIs, improving treatment success in gastroesophageal reflux disease (GERD).

Limitations of Pharmacogenomic Testing

✅ Key Considerations for PGT

• Genetic variation in African populations is underrepresented in research studies.
• Array-based genotyping only detects known alleles, missing rare genetic variations.
• PGT should always be interpreted alongside clinical history and other non-genetic factors.
• Standardisation of pharmacogenomic panels remains a challenge across different laboratories.

📌 PGT should complement clinical decision-making rather than replace traditional diagnostic approaches.

Key Takeaways for Clinicians

✅ PGT helps optimise drug therapy, reducing adverse reactions and improving treatment efficacy.
✅ Panel-based PGT (e.g., PGx120) offers cost-effective, comprehensive testing for multiple drug-gene interactions.
✅ CYP2D6 testing prevents opioid toxicity from codeine and tramadol.
✅ CYP2C9 and VKORC1 testing improves warfarin dosing and safety.
✅ SLCO1B1 testing minimises statin-associated muscle symptoms.
✅ CYP2C19 and CYP2D6 testing enhances antidepressant efficacy.
✅ CYP2C19 testing optimises PPI treatment for acid-related disorders.

📌 Pharmacogenomic testing represents a key advancement in personalised medicine, improving patient care and drug safety.