Table of Contents

PHENYTOIN PHARMACOKINETIC MONITORING

A. KINETIC PARAMETERS

 

Bioavailability (F): 0.90 - 1.0
Salt Factor (S): 0.92 - Phenytoin Na+ (caps, IV)

1.0 - Phenytoin Acid (tabs, susp)
Protein Binding: 90% (87-93)
Volume of Distribution (Vd): 0.7L/Kg - Adults

1.0L/Kg - Children
Half-Life (t½): a function of plasma concentration
average - 22 hours (range 8 - 60 hours)
Elimination: capacity limited metabolism (Zero order)
1-5% recovered unchanged in the urine
Cpss (SI): 40-80 umol/L (>20umol/L)
Time to Steady State: 1-4 weeks (longer with higher doses)
Conversion factor to metric: Divide by 4 to convert from umol/L to mg/L


B. DOSING  Empiric dosing guidelines (use TBW)

ROUTE

LOADING DOSE*

MAINTENANCE DOSE

IV

15-18 mg/kg - total dose direct at maximum rate of 50 mg/min 

OR

Dilute to 5-20 mg/mL with NS & give over 15-30 minutes

5-7 mg/kg/day - in 2 to 3 divided doses

IM

Not recommended

  

ORAL:

 

CAPSULES


 

SUSPENSION

NG TUBE

 

 

15-18 mg/kg PO/NG- given as 200-400 mg q2-3h

 

 

 

 

 

 

5-7 mg/kg/day in one daily dose
If > 400 mg/day - two doses

 

5-7 mg/kg/day in 2 to 3 doses

  • may need 2-4 times IV/PO dose

  • hold feeds 2 hrs before and after a single daily dose

  • Flush tube well with 50mL sterile water

* If Phenytoin level available prior to loading dose, use Equation 1:

Equation 1:

Loading Dose =

[Vd (Cp desired - Cp observed)]/FS

 

(NB: Must convert Cp to metric units ie. mg/L by dividing SI units by 4 )
 

C. MONITORING

1) Phenytoin Serum Levels
 

Loading Dose:

  • 2-4 hours post IV or 24 hours post PO load
Maintenance Dose:

  • steady state trough levels (7-21 days) or

  • compare two levels drawn at 2-4 day intervals (e.g. post loading dose level and compare to a follow-up level in 2-4 days); provides estimate of the accumulation or deficiency of a fixed maintenance dose
Seizure Activity:

  • at the time of a seizure, a phenytoin level helps to estimate a threshold for seizure activity

2) Serum Albumin
Phenytoin is approximately 90% protein bound. Reported levels are based on total phenytoin (bound + free) and levels must be adjusted when serum albumin is reduced:

Equation 2: 

Cp normal =

Cp observed / [(0.02 x albumin) + 0.1]

 

3) Renal Failure (<10mL/min, dialysis)
In patients with renal failure, uremia increases the unbound fraction of phenytoin. These patients also tend to have low serum albumin. In general, aim for therapeutic levels between 20-40 umol/L.

D. DOSAGE ADJUSTMENT
Phenytoin does NOT demonstrate a proportional relationship between drug levels and dose. Due to zero order kinetics, dosage should NOT be increased by more than 50-100mg increments.

OVERDOSE:
Hold dosage until levels are back within the therapeutic range then reduce dosage as per above. As a general rule, hold therapy 1 day for every 20umol/L over 80umol/L

E. TOXICITY
 

Dose Related: drowsiness, confusion, nystagmus, ataxia, slurred speech, nausea, unusual behavior, mental changes, coma

(levels > 200umol/L)

Non-Dose Related:

hirsutism, acne, gingival hyperplasia, folate deficiency, osteomalacia, hypersensitivity reactions (including Steven’s Johnson syndrome), SLE