### Pharmacogenetics: Clinical Overview for Healthcare Professionals

**Definition**

Pharmacogenetics (PGx) is the study of inherited variations in drug-metabolizing enzymes, transporters, and drug targets that influence inter-individual differences in efficacy and toxicity. These variations are stable, germline polymorphisms and are actionable at the point of prescribing.

**Primary Genes and Pathways**

Clinically relevant pharmacogenes include (but are not limited to):

- Phase I: CYP2D6, CYP2C19, CYP2C9, CYP3A4/5, CYP2B6

- Phase II: UGT1A1, TPMT, NUDT15, DPYD

- Transporters: SLCO1B1, ABCB1

- Targets/Receptors: VKORC1, HLA-B, IFNL3/4

**Metabolizer Phenotypes (Standardized CPIC Terminology)**

1. **Ultra-rapid Metabolizer (UM)** – Gene duplication or gain-of-function alleles → increased enzyme activity

→ Higher doses often required (or avoidance of prodrugs)

2. **Extensive (Normal) Metabolizer (EM)** – Two functional alleles → reference activity and standard dosing

3. **Intermediate Metabolizer (IM)** – One reduced-function + one non-functional allele (or two reduced-function alleles) → decreased activity

→ Dose reduction or alternative agent typically recommended

4. **Poor Metabolizer (PM)** – Two non-functional alleles → absent or near-absent activity

→ Significant dose reduction or complete avoidance required

**Clinical Impact**

- Up to 25–50 % of commonly prescribed medications (opioids, SSRIs/SNRIs, beta-blockers, statins, antiplate, anticoagulants, oncologics, etc.) are substrates of highly polymorphic pharmacogenes.

- Adverse drug reactions attributable to genetic variation are a leading cause of emergency department visits and hospitalizations.

- PGx-guided prescribing has Level 1 evidence (CPIC A/B, FDA “test recommended/required”) for >120 drug–gene pairs.

**One Tenacity PGx Panel – Key Features for Clinicians**

- Comprehensive coverage of all CPIC Level A and B genes plus emerging pharmacogenes

- Star allele/diplotype calling with full transparency (no black-box scoring)

- Actionable, guideline-driven recommendations aligned with CPIC, DPWG, FDA, and Health Canada

- Automatic lifetime re-analysis and alert generation when new guidelines or drug labels are published

- Secure clinician portal with EHR-friendly PDF reports and discrete data export options

- Full compliance with PIPEDA, HIPAA, and GDPR

**Evidence-Based Implementation**

All therapeutic recommendations are derived exclusively from peer-reviewed, consensus guidelines (CPIC, DPWG, FDA, Health Canada/Santé Canada). When evidence is insufficient for a formal recommendation, the report clearly states “no prescribing action recommended at this time.”

One Tenacity pharmacogenetic testing provides clinicians with reproducible, lifelong, patient-specific data to optimize drug selection and dosing from the very first prescription — reducing trial-and-error, minimizing toxicity, and improving therapeutic outcomes across the continuum of care.