Why In The News?

Pharmacogenomics is transforming healthcare by showing how genetic differences affect individual drug responses. This breakthrough emerging technology is replacing traditional “start low, go slow” trial-and-error prescribing with personalised, precision-based treatment that improves effectiveness and reduces harmful reactions.

1) What is Pharmacogenomics?

• Definition & Purpose: Studies how genetic variations affect drug response, determining whether a drug will be effective, ineffective, or harmful.
• Role of Enzymes: Differences in drug-metabolising enzymes, especially the CYP450 family, impact the metabolism of ~75% of common drugs.
• Metaboliser Phenotypes:
  • Poor Metaboliser: Low enzyme activity → toxic drug buildup at standard doses.
  • Ultrarapid Metaboliser: High enzyme activity → reduced therapeutic benefit.
• Widespread Variants: About 90% of people carry at least one actionable pharmacogenetic variant.
• Clinical Impact: Genetic factors significantly contribute to adverse drug reactions (ADRs), a major cause of hospitalisation and death in developed nations.

2) Understanding the Problem in Traditional Prescribing:

• Traditional Approach – “Start Low, Go Slow”: Reflects the challenge that the same drug and dose can heal one patient but harm another.
• Population-Based Prescribing: For decades, medications were prescribed based on population averages, leading to trial-and-error treatment.
• Shift Toward Precision: Pharmacogenomics is transforming this approach by showing how genes influence drug response, moving from guesswork to precision.

3) Real-World Applications:

• Warfarin Dosing:
  • Variants in CYP2C9 and VKORC1 explain ~50% of dose variation.
  • Genetic-guided dosing reduces bleeding risk and allows faster achievement of therapeutic levels.
• Clopidogrel Activation:
  • Requires CYP2C19 for activation.
  • CYP2C19*2 variants (25–30%) → poor activation → higher risk of stent thrombosis.
  • CPIC 2022 guidelines recommend alternatives for poor metabolisers.
• Psychiatry:
  • Many antidepressants/antipsychotics rely on CYP2D6 and CYP2C19.
  • Testing reduces side effects, improves symptom control, and lowers costs.
• Oncology: Rapid progress in using genetic markers to personalise cancer treatment.

4) Economic Considerations:

• Cost Reduction: Genetic test prices have dropped from thousands to $200-500 for large panels.
• Cost–Effectiveness:
  • Testing prevents adverse events and improves outcomes, proving cost-effective, especially in chronic diseases.
• Evaluation Framework: Value depends on factors such as severity of side-effects, frequency of variants, availability of alternative drugs, and variability in clinical settings.
• Preventive Value: Avoiding even one serious ADR can offset the cost of testing many patients.

5) Implementation Challenges:

• Provider Knowledge Gaps: Most clinicians lack training in pharmacogenomics, making interpretation difficult.
• Infrastructure Limitations: Electronic health records often lack tools to integrate genetic data into prescribing workflows.
• Reimbursement Issues: Insurance coverage remains inconsistent, creating hesitation.
• Regulatory Complexity:
  • Over 100 FDA drug labels include pharmacogenomic information.
  • Some provide actionable guidance; others are only informative.
• Cultural & Institutional Barriers: Requires changes in clinical culture, administrative support, and trained champions to lead adoption.

6) The Path Forward:

• Pre-emptive Testing: Future lies in obtaining genetic profiles before medications are needed, enabling lifelong personalised prescribing.
• Fundamental Shift: Moves healthcare from population-based to individualised, from reactive to proactive, and from trial-and-error to precision medication.
• Genomic Insight: Our genes guide our prescriptions-pharmacogenomics teaches us how to read this biological roadmap.

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