Phenytoin & Fosphenytoin Dosing Information

Clinical Usage

Indications: Tonic-clonic and complex partial seizures, seizure prophylaxis after neurosurgery.

Distribution: Brain and CSF levels are similar to unbound plasma levels.

Pharmacokinetic Parameters

Oral Bioavailability (F)	100% (F=1), slow-release formulations 100% (F=1)
IV Fraction (F)	1
Salt (S)	Phenytoin sodium/fosphenytoin 92% (S=0.92), Phenytoin acid as suspension and chewable tablet (S=1)
Route of Administration	Phenytoin IV/Oral, Fosphenytoin IV/IM
Rate of Administration	Phenytoin IV: Maximum 50 mg/min in adults, 0.5 mg/kg/min neonates, 1 mg/kg/min for pediatric and adolescents and adults Fosphenytoin IV: 150 mg PE/min in adults, 3 mg PE/kg/min children and adolescents
Peak Concentrations	2 hours after IV at end of infusion 4 hours after Fosphenytoin IM injection Oral non-extended release: several hours after dose Phenytoin extended-release time to peak is dose-dependent: 400 mg: 8.4 hours 800 mg: 13.2 hours 1600 mg: 31.5 hours Oral loading doses of extended-release: 24-30 hours post-dose
Protein Binding	90% bound to albumin, fraction unbound 0.1. Alterations in plasma binding require an adjustment of plasma concentrations for the change in bound concentration as assays measure total concentrations (bound + unbound). Hypoalbuminemia and end-stage renal failure affect plasma protein binding.
Metabolism	Capacity-limited hepatic metabolism, 90% CYP2C9, 10% CYP2C19, less than 5% is excreted renally. 90% of people are genetically classified as normal/extensive metabolizers of phenytoin, 10% of people are CYP2C9 heterozygous or intermediate metabolizers, and 1% are homozygous CYP2C9 or poor metabolizers.
Genetics	HLA-B15:02 gene carrier has a higher risk of toxic epidermal necrolysis and Stevens-Johnson syndrome
Vd (Volume of Distribution, L/kg)	Neonates and infants (< 1 year): 1 L/kg Children and adults: Normal: 0.65 L/kg of ideal body weight Obese: 0.65 × (Ideal body weight + 1.33 × (Total body weight - Ideal body weight))
V_max (Maximum Rate of Metabolism, mg/hour)	Should be based on ideal weight if total weight is greater. If the rate of intake is greater than V_m, levels continually increase. V_max will increase with enzyme inducers (carbamazepine, phenobarbital) and levels will decrease. V_max will decrease in liver disease (cirrhosis) and levels will increase. Typical values are for normal/extensive metabolizers.
K_m (Michaelis-Menten Constant, mg/L)	K_m is a dissociation constant and its reciprocal is the expression of binding affinity. K_m increases as affinity decreases. K_m is the plasma concentration at which metabolism is half the maximum rate. K_m is increased by competitive inhibitors (e.g. cimetidine, valproic acid, fluoxetine) and phenytoin levels will increase. K_m is decreased by decreased protein binding (lower serum albumin) and displacement from plasma proteins (valproic acid, salicylate, sulfisoxazole) and total phenytoin serum levels will decrease. K_m is calculated based on total plasma phenytoin concentrations.
Clearance (L/hour)	Cl = V_max / (K_m + Cp), decreases with increasing serum concentrations
Elimination Rate Constant (1/hours)	K = (V_max / (K_m + Cp)) / Vd, decreases with increasing concentrations
Half-life (hours)	t_½ = 0.693 / K, as concentration increases half-life increases
Dosage Forms	Injection, tablets, capsules, suspension
Usual Interval	Every 6, 8, 12, 24 hours

Usual Oral Dose Maintenance Therapy

Use ideal body weight to calculate the dose in the obese, usually in divided doses unless oral extended-release is administered. Normal/extensive metabolizers receive the full dose, intermediate metabolizers receive 75% and poor receive 50% of the normal dose.

Neonates (< 4 weeks): 3-5 mg/kg/day
Infants (4 weeks - <1 year): 4-8 mg/kg/day
Children (1 to less than 12 years): 4-10 mg/kg/day
Adolescents (12 - <18 years): 4-8 mg/kg/day
Adults: 4-7 mg/kg/day

Loading Dose

Do not adjust the initial loading dose for protein binding when no drug is on board as the desired concentrations decrease proportionally to protein binding. BP and heart rate should be monitored during the loading dose. If drug is on board the current total level and desired level must be adjusted to equivalent levels for normal protein binding (see equation below).

Loading Dose Regimens:

Neonates (< 1 year): IV 15-20 mg/kg in divided doses every 2 hours; oral give 5 mg/kg every 2 hours until total load administered
Children (1 - <12 years): IV 15-18 mg/kg in divided doses every 2 hours; oral give 5 mg/kg every 2 hours until total load administered
Adolescents and Adults: IV 15-18 mg/kg given in divided doses every 2 hours; oral give 5 mg/kg every 2 hours until total load administered

Intravenous Supplement for Suboptimal Level:

Dose (mg) = 0.65 L/kg × Loading Dose Weight (kg) × (Cp_{desired Equivalent Normal Binding} - Cp_{observed Equivalent Normal Binding})

Therapeutic Levels & Monitoring

Therapeutic Range:

Total phenytoin (free and bound): 10-20 mg/L
Free phenytoin: 1-2 mg/L

Serum Sampling Times and Recommended Monitoring:

Peak:

2 hours after IV injection to allow for distribution of phenytoin
4 hours after fosphenytoin (IV or IM) to allow for distribution and hydrolysis
24 hours after oral loading dose

Trough: Suggested for routine monitoring

Every 2-3 days during initiation of therapy
Weekly until stable levels are achieved
Monthly, then every 3-12 months

Empirical Dose Adjustments

Assumes the patient is currently receiving at least 300 mg/day

Serum Level (mg/L)	Dose Increase	Conservative Approach
< 7 mg/L	100 mg/day	50-75 mg/day
7-12 mg/L	50 mg/day	30-50 mg/day
> 12 mg/L	30 mg/day	30 mg/day

Extracorporeal Clearance

Hemodialysis:

Removes little phenytoin as the unbound volume of distribution is extremely large (6.5 L/kg).

Continuous Renal Replacement Therapy (CRRT):

Removal (mg) = Effluent Flow (L/hr) × Hours of CRRT × Unbound Concentration (mg/L)

Plasmapheresis or Plasma Exchange:

5-10% loss during plasmapheresis as most phenytoin (95%) is in the tissue compartment.

Side Effects & Toxicity

Infusion-Related:

High infusion rate can cause bradycardia, hypotension, widened PR, QRS, or QT intervals.

Concentration-Dependent Toxicity:

Nystagmus, ataxia, slurred speech, confusion, and coma may occur as levels increase.

Pharmacokinetic Model:

One-compartment non-linear with capacity-limited metabolism (non-dose proportionality).

Common Drug Interactions

Decreased Absorption:

Antacids, cisplatin, tube feedings

Decreased Clearance (Increased Levels):

Enzyme inhibitors: amiodarone, chloramphenicol, cimetidine, disulfiram, fluconazole, fluoxetine, isoniazid, phenylbutazone, sertraline, sulfonamides, ticlopidine, trimethoprim, voriconazole

Increased Clearance (Decreased Levels):

Enzyme inducers: carbamazepine, ciprofloxacin, folic acid (reduced K_m), rifampin

Protein Binding Displacement Interactions:

Salicylates (>50 mg/L), sulfonamides, valproic acid

Disease State or Physiologic Condition Interactions:

Decreased clearance: Cirrhosis
Increased clearance: Pregnancy

Dosage Calculations

Ideal Body Weight (Devine Formula):

Adult Males (≥18 years):

IBW (kg) = 50 kg + 2.3 × (Height in inches greater than 60 inches)

Adult Females (≥18 years):

IBW (kg) = 45.5 kg + 2.3 × (Height in inches greater than 60 inches)

Adjusted Body Weight (for Vd Calculation):

Adjusted Body Weight (kg) = IBW + 1.33 × (Total Body Weight - IBW)

Dosing Weight:

V_d: Use Adjusted Body Weight if total body weight is larger than IBW
V_max: Use IBW if total body weight is larger than IBW

Clearance:

Cl (L/hr) = V_max (mg/hr) / (K_m (mg/L) + Css_avg (mg/L))

Clearance decreases with increasing concentrations

Volume of Distribution:

Normal: Vd (L) = 0.65 × Ideal Body Weight (kg)

Obese: Vd (L) = 0.65 × (Ideal Body Weight + 1.33 × (Actual Body Weight - Ideal Body Weight))

Elimination Rate Constant:

K (1/hr) = Cl / Vd = (V_m / (K_m + Cp)) / Vd = V_m / ((K_m + Cp) × Vd)

Half-life:

t_½ = 0.693 × Vd (L) × (K_m (mg/L) + Cp (mg/L)) / V_max (mg/hr)

Increases with increasing levels

Maintenance Dose:

Dose (mg) = (V_max (mg/hr) × Css_avg (mg/L) × Tau) / (S × F × (K_m (mg/L) + Cpss_avg (mg/L)))

Average Steady-State Concentration:

Cp_average (mg/L) = K_m (mg/L) × (S × F × Dose (mg) / Tau) / (V_max (mg/hr) - (S × F × Dose (mg) / Tau))

Concentration Adjustment for Protein Binding

Protein binding is altered by hypoalbuminemia, renal failure and displacement by other medications. Adjustments are required in conditions with decreased albumin: burns, hepatic cirrhosis, nephritic syndrome, pregnancy, cystic fibrosis, and in conditions with decreased affinity for albumin: renal failure, severe jaundice, and drug displacement interactions.

Note: When creatinine clearance is above 25 mL/min no adjustments are required for renal dysfunction. Patients with creatinine clearance 10-25 mL/min have unpredicted binding and a free & total pair are recommended.

Adjustment Formulas:

Non-dialysis patient:

Concentration equivalent to normal protein binding = Cp_measured / ([(0.9 × (albumin_patient / 4.4)] + 0.1)

Hemodialysis patient:

Concentration equivalent to normal protein binding = Cp_measured / ([(0.9 × 0.48 × (albumin_patient / 4.4)] + 0.1)

With known total and free level pair:

Concentration equivalent to normal protein binding = measured level × (free level / total level) / 0.1

Concurrent Valproic Acid (Cp >20 mg/L):

Concentration equivalent to normal protein binding = (0.095 + 0.001 × Valproic Acid Cp) × (phenytoin Cp) / 0.1

Note: Draw both levels at the same time

Time to Change in Serum Level During Consistent Dosing

Time to steady state is dependent on the rate of administration, K_m and V_max.

Time Between Two Concentration Levels:

Time = (Vd / (V_max - R_in)) × (K_m × V_max / (V_max - R_in)) × Ln[(R_in × K_m - (V_max - R_in) × Cp1) / (R_in × K_m - (V_max - R_in) × Cp2)]

Time to 90% of Steady State:

Time (hours) = (K_m (mg/L) × Vd (L) / [V_max (mg/hr) - S × F × (Dose (mg) / Tau)]²) × (2.3 × V_max (mg/hr) - 0.9 × S × F × (Dose (mg) / Tau))

Time for Level to Decline:

Time (hours) = [(K_m (mg/L) × (Ln(C1 (mg/L) / C2 (mg/L))) + (C1 (mg/L) - C2 (mg/L))] / (V_max (mg/hr) / Vd (L))

Assumes drug has been stopped and no further absorption during the time interval. This equation is best used with IV dosing due to the prolonged time of oral absorption.

Determination of Pharmacokinetic Parameters

Mass Balance Calculation to Determine V_max with Two Non-Steady State Levels:

Requires consistent dosage rate

Principle: Amount of drug change in body / Time = Rate of administration - Rate of Metabolism

Step 1 - Calculate amount eliminated:

Amount of elimination (mg/hr) = (S × F × Dose / Tau) - (((Cp2 - Cp1) × Vd (L)) / (Hours between Cp2 and Cp1))

Step 2 - Calculate V_max (K_m must be assumed):

V_max (mg/hr) = [Amount eliminated (mg/hr) × (K_m + ((Cp1 + Cp2) / 2))] / ((Cp1 + Cp2) / 2)

Combined formula:

V_max (mg/hr) = [(S × F × Dose / Tau) - (((Cp2 - Cp1) × Vd (L)) / (Hours between Cp2 and Cp1)) × (K_m + ((Cp1 + Cp2) / 2))] / ((Cp1 + Cp2) / 2)

Caveats for using the mass balance equation:

The time between levels should be greater than or equal to 3 days
If levels are increasing: C2 should be < 2 × C1
If levels are decreasing: C2 should be > ½ × C1

Determining V_max Using One Known Steady State Level:

V_max (mg/hr) = S × F × Dose (mg) / Tau (hours) × (K_m (mg/L) + Cpss_avg (mg/L)) / Cpss_avg (mg/L)

K_m must be assumed

K_m and V_max Determination Using Two Known Steady State Levels from Two Different Dosage Rates:

K_m (mg/L) = -(S × F × Dose1 / Tau1 - S × F × Dose2 / Tau2) / [(S × F × D1 / (Tau1 × Cpss1)) - (S × F × D2 / (Tau2 × Cpss2))]

Then calculate V_max:

V_max (mg/hr) = S × F × Dose (mg) / Tau (hours) × (K_m (mg/L) + Cpss_avg (mg/L)) / Cpss_avg (mg/L)

Dose can be either dose one or dose two with the corresponding Cpss_avg

Explicit Solution Using Lambert W-Omega Function

One-Compartment Pharmacokinetic Bolus Model with Michaelis-Menten Elimination using Lambert W-Omega Function

Lambert W-Omega Function:

W(x) = 1.4586887 × ln((1.2 × x) / ln(2.4 × x / ln(1 + 2.4 × x))) - 0.4586887 × ln(2 × x / ln(1 + 2 × x))

For a Single Bolus Dose or Declining Levels:

C(t) = K_m × W(x)

Where: x = Co / K_m × exp((Co - V_max / Vd × t) / K_m)

Co is the starting concentration and t is the time of level post concentration. If a bolus is given at time zero, Co = Dose / Vd. The value of the expression in the brackets is x to be placed in the Lambert W-Omega Function.

Steady State Levels for a Periodic Dose at Set Interval:

Z = Dose / (Vd × (1 - exp((Dose - V_max × Tau) / (K_m × Vd))))

Css_min = K_m × W[Z / K_m × exp((Z - (V_max / Vd) × Tau) / K_m)]

Css_max = K_m × W[Z / K_m × exp((Z - (V_max / Vd) × Tau) / K_m)] + Dose / Vd

The value of the expression in the brackets is x to be placed in the Lambert W-Omega function. The result of W(x) is placed in the Css_min and Css_max equations.

Phenytoin & Fosphenytoin Pharmacokinetic Dosing Information