Usage: Tonic-clonic and complex partial seizures, seizure
prophylaxis after neurosurgery. Brain and CSF levels are similar to unbound
plasma levels.
Oral Bioavailability (F):
100% (F=1), slow-release formulations 100% (F=1).
IV fraction (F):
1
Salt: 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 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 carries has a higher risk of toxic epidermal necrolysis
and Stevens-Johnson syndrome
Vd (L/kg):
Neonates and infants (< 1year):
1 L/kg
Children and adults:
Normal 0.65
L/kg of ideal body weight (kg)
Obese
0.65 * (Ideal body weight + 1.33*(Total body weight - Ideal body weight))
Vmax (mg/hour): Maximum rate of metabolism, should be based on
ideal weight if total weight is greater. If the rate of intake is greater than Vm levels continually increase. Vmax will increase with enzyme inducers (carbamazepine,
phenobarbital) and levels will
decrease. Vmax will decrease in liver disease (cirrhosis) and levels will increase.
Typical values are for normal/extensive metabolizers.
Km (mg/L):
Km is a dissociation constant and its reciprocal is the expression of binding
affinity. Km increases as affinity decreases. Km is the plasma concentration at which metabolism is half the maximum rate.
Km is increased by competitive inhibitors (e.g. cimetidine, valproic acid,
fluoxetine) and phenytoin levels will increase. Km 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.
Km is calculated based on total plasma phenytoin concentrations
Cl (L/hour): Vmax / (Km + Cp), decreases with increasing
serum concentrations
K (1/hours): (Vmax/(Km + Cp))/Vd, decreases with increasing
concentrations
Half-life (hours): 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 -
<1year):
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).
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 IV given in divided doses every two hours, oral give 5 mg/kg
every 2 hours until total load administered
Intravenous Supplement for
suboptimal level (mg): 0.65l/kg*Loading Dose Weightkg* (Cpmg/L
desired Equivalent Normal Binding - Cpmg/Lobserved Equivalent Normal
Binding).
Therapeutic Levels: 10-20 mg/L (total free and bound phenytoin), 1-2 mg/L free
Serum Sampling Times and Recommended Monitoring: Peak: 2 hours after
IV injection to allow for distribution of phenytoin and 4 hours after
fosphenytoin to allow for distribution and hydrolysis of fosphenytoin. Four (4) hours after intramuscular administration of fosphenytoin.
Twenty four hours after oral loading dose. Troughs are suggested for routine monitoring.
Trough every 2-3 days during initiation of therapy, then weekly until stable
levels are achieved, then monthly, then every 3-12 months.
Empirical Dose
Adjustments: assumes the patient is currently receiving at least 300 mg/day
Serum level < 7 mg/L increase by 100 mg/day (a more conservative approach is
50-75 mg/day)
Serum level 7-12 mg/L increase by 50 mg/day (a more
conservative approach is 30-50 mg/day)
Serum level > 12 mg/L increase by 30
mg/day (30 mg/day)
Hemodialysis: removes little phenytoin as the unbound volume of distribution is
extremely large 6.5 L/kg.
Continuous Renal Replacement Therapy
Removal(mg) = (Effluent FlowL/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
Pharmacokinetic Model: one-compartment non-linear with capacity-limited
metabolism (non-dose proportionality)
Side effects:
high infusion rate can cause bradycardia, hypotension, widened PR, QRS, or QT
intervals. Nystagmus, ataxia, slurred speech, confusion, and coma may occur as
levels increase.
Toxicity:
Common Drug interactions:
Decreased absorption: antacids,
cisplatin, tube feedings
Decrease clearance: enzyme inhibitors, amiodarone,
chloramphenicol, cimetidine, disulfiram, fluconazole, fluoxetine, isoniazid, phenylbutazone, sertraline, sulfonamides, ticlopidine,
trimethoprim, voriconazole
Increased clearance:
enzyme inducers, carbamazepine, ciprofloxacin, folic acid (reduced Km), rifampin
Protein binding
displacement interactions: salicylates (>50mg/L), sulfonamides, valproic acid
Disease state or physiologic condition interactions:
Decrease
clearance: cirrhosis
Increase clearance:
pregnancy
Dosage Calculations
Ideal Body Weight
IBW(kg) (Devine Formula)
Adult Males (18 years and older) in kg: 50 kg + 2.3*(Height in inches greater
than 60 inches)
IBW(kg) (Devine Formula) Adult Female (18 years and older): 45.5 + 2.3*(Height in
inches greater than 60 inches)
Adjusted Body Weight (kg) Used
for Vd Calculation
= IBW + 1.33* (Total Body Weight - IBW)
Dosing Weight(kg) =
Vd - Use Adjusted Body Weight if total body weight is larger
than IBW
Vmax - Use IBW if total body weight is
larger than IBW
Clearance(L/hr) = Vmaxmg/hr / ( Kmmg/L+ Cssavgmg/L), Clearance decreases
with increasing concentrations
Volume of Distribution(L)
Vd(liters) = 0.65 * Ideal Body Weight (kg)
Obese = 0.65*(Ideal Body Weight + 1.33 (Actual
Body Weight - Ideal Body Weight))
K(1/hours) = Clearance / Vd = (Vm/(Km
+ Cp))/Vd = Vm/((Km +Cp)*Vd)
T1/2 = 0.693*VdL* (Kmmg/L+Cpmg/L)/Vmmg/hr ,
increases with increasing levels
Maintenance Dose(mg) =
(Vmaxmg/hr*Cssavgmg/L*Tau) / (S*F* (Kmmg/L+Cpssavgmg/L))
Cpaverage(mg/L)
= Kmmg/L*(S*F*Dosemg/Tau) / (Vmaxmg/hr - (S*F*Dosemg/Tau))
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 future level
may be calculated using the following equations
C(t) = Km * W(x)
C(t) = Km * W[Co/Km *exp((Co-Vmax/Vd*t)/Km)] where Co in 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 or first equation. The result is W(x) which is replaced in the second equation. The third equation shows the complete expression. Simple but confusing.
Steady State Levels for a period dose at a set interval
Z = Dose/(Vd*(1-exp((Dose-Vmax*Tau)/(Km*Vd))))
Cssmin = Km * W[Z/Km *exp ((Z-(Vmax/Vd)*Tau)/Km)]
Cssmax = Km*W[Z/Km*exp((Z-(Vmax/Vd)*Tau)/Km)] + 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 Cssmin and Cssmax equations.
Suggested Readings for Lambert W-Omega Function
Golicnik M. Exact and Approximate Solutions for the decades old Michaelis-Menten Equation: Progress-curve Analysis Through Integrated Rate Equations. Biochemistry and Molecular Biology Education 2011; 39:117-125
Golicnik Marko Explicit reformulations of the Lambert W-Omega function for calculations of the solutions to one-compartment pharmacokineti model with Michaelis-Menten elimination kinetics. Eur J Drug Metab Pharmacokinet 2011;36:121-127
Tang S Xiao Y. One-compartment model with Michaelis-Menten elimination kinetics and therapeutic window: an analytical approach. J Pharmacokinet Pharmacodyn. 2007;34;807-827
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