Phenytoin Dosing in Renal Impairment
No renal dose adjustment is required for phenytoin based on glomerular filtration rate, but therapeutic drug monitoring is essential because renal impairment significantly alters protein binding and increases free (active) drug concentrations.
Key Pharmacokinetic Principle
Phenytoin is primarily metabolized by the liver (not renally eliminated), so the total daily dose does not need to be reduced in renal failure 1. However, renal impairment creates a critical clinical challenge:
- Protein binding is substantially reduced in patients with renal insufficiency, particularly when creatinine clearance falls below 25 mL/min 1
- This results in disproportionately high free (unbound) phenytoin concentrations relative to total serum levels 2, 1
- The free fraction is the therapeutically active component that produces both efficacy and toxicity 2
Monitoring Strategy
Monitor free (unbound) phenytoin levels rather than total phenytoin levels in patients with renal impairment 2, 1. This is the most important clinical action:
- Total phenytoin levels will appear falsely low due to decreased protein binding 2
- Free phenytoin concentrations correlate with clinical effect and toxicity 2
- Salivary phenytoin concentrations closely correlate with free plasma levels and can be used as a non-invasive monitoring alternative 2
- The optimal therapeutic range for salivary phenytoin is 4-10 μmol/L 2
Dose Adjustment Approach
Do not routinely reduce phenytoin doses based solely on creatinine clearance 1. Instead:
- Start with standard dosing
- Measure free phenytoin concentrations (or salivary levels) 2, 1
- Adjust doses based on free drug levels and clinical response
- Calculate equivalent therapeutic concentrations using serum albumin and renal function parameters 1
Special Considerations
Continuous Hemofiltration
In critically ill patients receiving continuous hemofiltration 3:
- Phenytoin removal is generally minimal at low ultrafiltration rates
- At high ultrafiltration rates with reduced protein binding, clinically significant drug removal can occur 3
- Higher daily doses may be needed to maintain therapeutic effect 3
- Therapeutic drug monitoring is mandatory to determine optimal dosing 3
CYP3A4 Interactions
Moderate-to-severe renal impairment (creatinine clearance <30 mL/min) may affect hepatic metabolism of drugs metabolized by CYP3A4 when used concomitantly with phenytoin 4. Dose adjustment based on therapeutic drug monitoring is necessary for these combinations 4.
Common Pitfall to Avoid
Do not interpret low total phenytoin levels as subtherapeutic in renal failure patients 2, 1. The free drug concentration may be adequate or even excessive despite low total levels. Increasing the dose based on total levels alone can lead to toxicity 2, 1.