What are the therapeutic serum phenytoin concentrations and recommended loading and maintenance doses, and how should they be adjusted in patients with low albumin or renal impairment?

Therapeutic Phenytoin Levels and Dosing

The therapeutic total serum phenytoin concentration is 10–20 µg/mL (40–80 µmol/L), with a corresponding free (unbound) concentration of 1–2 µg/mL, though individual patients may require levels above 15 µg/mL or even higher for optimal seizure control. 1, 2

Standard Therapeutic Range

• Total phenytoin: 10–20 µg/mL (40–80 µmol/L) 1, 2
• Free phenytoin: 1–2 µg/mL 1, 3
• Approximately 51% of patients achieve complete seizure control at concentrations either below or above the standard 10–20 µg/mL range, emphasizing that clinical response trumps rigid adherence to reference ranges 4
• Some patients require concentrations above 15 µg/mL or even twice the upper therapeutic limit (up to 160 µmol/L) for adequate seizure control without toxicity 2, 5

Loading Dose Regimens

Intravenous Loading

• Administer 18–20 mg/kg IV at a maximum rate of 50 mg/min in adults 1, 6, 3
• In pediatric patients, use 15–20 mg/kg at 1–3 mg/kg/min (or 50 mg/min, whichever is slower) 3
• Fosphenytoin offers significant advantages: can be administered at 150 PE/min (three times faster than phenytoin) with fewer adverse events and is now available generically 1, 2
• Continuous cardiac monitoring, blood pressure monitoring, and respiratory function assessment are mandatory during IV infusion 6, 3
• Therapeutic levels are achieved within 10 minutes of IV loading completion, but check levels at 2–4 hours to confirm sustained therapeutic concentrations 2
• Critical monitoring point: approximately 50% of patients have subtherapeutic levels at 12 hours post-loading 1, 2

Oral Loading

• Administer 18–20 mg/kg divided into maximum doses of 400 mg every 2 hours 1, 6
• Therapeutic levels are generally achieved within 3–8 hours after oral administration 2
• Oral loading is safer and significantly cheaper than IV, with no difference in seizure recurrence rates between routes 6
• Use in awake, cooperative patients who do not require immediate seizure control 1

Maintenance Dosing

• Standard maintenance: 300–400 mg/day (4–6 mg/kg/day) divided into 1–3 doses, or as a single daily dose 2, 6, 3
• Typical maintenance range is 200–700 mg/day depending on individual factors 2
• Dose adjustments: increase by 100–200 mg/day at weekly intervals when subtherapeutic, monitoring for efficacy and toxicity 1, 6
• Maximum typical adult dose is 1200 mg/day 1, 2
• Because phenytoin exhibits non-linear (Michaelis-Menten) kinetics, small dose increments of approximately 25 mg are appropriate once serum concentrations reach 5–10 µg/mL to avoid overshooting into toxic ranges 7

Adjustments for Low Albumin

In hypoalbuminemic patients, measure free phenytoin concentrations rather than relying on calculated values or total concentrations. 8

• The free fraction of phenytoin is normally 13.7% (range 8.9–27.0%) but increases significantly when albumin is low 9
• There is a strong negative correlation between serum albumin and free phenytoin fraction (r = -0.68, p < 0.001) 9
• Hypoalbuminemic patients (albumin < 3.5 g/dL) more frequently show >20% difference between measured and calculated free phenytoin levels 8
• The Sheiner-Tozer equation for calculating free phenytoin is unreliable in hypoalbuminemia—direct measurement is necessary 8
• Free phenytoin concentrations correlate better with clinical response and toxicity than total concentrations in patients with altered protein binding 9
• In 14.2% of patients with reduced protein binding, free phenytoin concentrations were better related to clinical effect than total concentrations 9

Adjustments for Renal Impairment

Monitor unbound (free) phenytoin concentrations in patients with renal disease, as the fraction of unbound drug is increased. 3

• Base therapeutic drug monitoring on the unbound fraction rather than total serum concentrations 3
• The free fraction exceeds 18% in approximately 18% of serum samples, commonly due to renal disease (along with hypoalbuminemia and liver disease) 9
• Phenytoin clearance decreases slightly in elderly patients, who often have concurrent renal impairment—lower or less frequent dosing may be required 3
• Intramuscular administration should be avoided due to erratic absorption, but if necessary, use a dose 50% greater than the oral dose and reduce by 50% when returning to oral therapy 3

Monitoring Strategy

• Check phenytoin levels 2–4 hours after IV loading to confirm therapeutic range achievement 1, 2
• Recheck at 12 hours post-loading, as 50% of patients may be subtherapeutic at this point 1, 2
• At steady state (without loading), regular oral dosing takes 3–7 days to achieve therapeutic levels 2
• In patients with hepatic or renal impairment, monitor more frequently 2
• Monitor for dose-related adverse effects: ataxia, nystagmus, tremor, somnolence, and cognitive impairment 1, 2

Common Pitfalls

• Do not treat serum concentration "numbers" rigidly—individualize therapy based on clinical response and adverse effects 5
• Free phenytoin concentration is particularly important for assessing toxicity: in patients with toxicity, total phenytoin was >80 µmol/L in only 42.9% of cases, while free phenytoin was >8 µmol/L in 85.7% (p < 0.05) 9
• Patients with higher seizure frequency at epilepsy onset or prior to treatment more often require higher therapeutic plasma concentrations (≥15 µg/mL phenytoin) 4
• When switching between phenytoin sodium salt and free acid formulations, adjust for the approximately 8% difference in drug content and monitor serum levels 3