Phenytoin Therapeutic Range
The therapeutic range for total serum phenytoin is 10-20 mcg/mL (or 40-80 micromol/L), with free phenytoin levels of 1-2 mcg/mL. 1
Standard Therapeutic Parameters
Total serum phenytoin: The FDA-approved therapeutic range is 10-20 mcg/mL, which represents the concentration at which optimum seizure control occurs without clinical signs of toxicity in most patients 1
Free phenytoin levels: The therapeutic target for unbound (free) phenytoin is 1-2 mcg/mL 2
Timing of level checks: Trough levels should be obtained just prior to the next scheduled dose to assess therapeutic range and patient compliance, while peak levels occur 4-12 hours after oral administration of Dilantin capsules 1
Clinical Context and Individual Variation
While the 10-20 mcg/mL range serves as the standard reference, clinical response must take precedence over numerical targets. The evidence reveals substantial individual variation:
Lower effective concentrations: Some patients, particularly those with infrequent primary tonic-clonic seizures, achieve complete seizure control with levels below 10 mcg/mL 3, 4
Higher concentrations when needed: Patients with partial epilepsies, complex partial seizures, or higher baseline seizure frequency often require concentrations at the upper end or above 15 mcg/mL for adequate control 4
Supratherapeutic levels: In rare cases, patients may require concentrations up to 160 micromol/L (approximately 40 mcg/mL) to control seizures, provided they tolerate these levels without significant toxicity beyond nystagmus 5
Monitoring Strategy After Loading
After IV loading doses (15-18 mg/kg):
- Therapeutic levels are achieved within 10 minutes of rapid IV infusion completion 2
- Levels should be checked 2-4 hours after completion to confirm sustained therapeutic concentrations 2
- Approximately 50% of patients may have subtherapeutic levels at 12 hours post-loading, making this a critical monitoring timepoint 2
- Most patients (approximately 83%) maintain therapeutic levels at 24 hours after appropriate loading 2
After oral loading doses:
- Therapeutic levels are generally achieved within 3-8 hours after administration 2
- Studies show 48-55% of patients achieve therapeutic levels by 3-10 hours post-ingestion 6
Critical Dosing Considerations
Steady-state timing: With regular maintenance dosing (without loading), 7-10 days (5-7 half-lives) are required to achieve steady-state levels 1
Saturable kinetics: Because phenytoin exhibits Michaelis-Menten (saturable) kinetics at therapeutic concentrations, small dose increases of 10% or more can produce disproportionately large increases in serum levels and potential toxicity 1
Dose adjustments: When levels reach 5-10 mcg/mL, subsequent adjustments should be made in small increments of approximately 25 mg rather than the typical 100 mg steps to avoid overshooting the therapeutic range 7
Common Pitfalls
Treating numbers instead of patients: In one study, 51% of patients on phenytoin monotherapy achieved complete seizure control at levels either below or above the 10-20 mcg/mL range, emphasizing that clinical judgment supersedes rigid adherence to reference ranges 4
Protein binding variations: Since phenytoin is highly protein-bound, free phenytoin levels may be altered in patients with hypoalbuminemia, renal disease, or other conditions affecting protein binding; in these cases, free phenytoin levels provide more accurate assessment 1
Premature level checks: Serum levels obtained before steady-state (less than 5-7 half-lives after initiation or dose change) are unreliable for therapeutic decision-making 1