Phenytoin dosing guidelines

Copyright – D. McAuley, GlobalRPh Inc., All Rights Reserved.
This initial program provides some general dosage guidelines based on population averages for the Michaelis-Menten parameters (Km and Vmax).  The recommendations do not take into account the following: (1) existence of interacting drugs (3) inter-patient variability (3) existing disease states  which may significantly alter the eventual therapeutic dose.

The program uses a maintenance dose of 4 to 6 mg/kg for all adults < 60 years old. The elderly (defined as age>60) on the other hand, exhibit a saturation of metabolism at dosages that are usually 20 % lower than in younger patients. For this reason, the program recommends initial dosages of 3-4 mg/kg in this age group. (Note: many studies have found only slight variations in Km with regards to age, however, Vmax has been found to decline steadily with age–most notably after the 6th decade).  The program also calculates an “adjusted dose” for reported levels when the serum albumin level is < 4.5 g/dl. The program accomplishes this by utilizing the Sheiner-Tozer equation: C adj = Creported /(0.2 x serum albumin) + 0.1.

In order to simplify the program, all dosages are based on the adjusted body weight. This is especially important in obese patients where the utilization of total body weight would result in an over-estimation of dosage.  Projected loading doses required to increase sub-therapeutic concentrations to the therapeutic range are determined by using the following equation: Cadj = (Concentration desired – Concentration observed) x Vd,   where Vd = 0.7 x adjusted body weight. The usual range for Vd is 0.52 to 0.78 L/kg.   I must stress again the general nature of this program. Significant inter-patient variability may exist for many of the pharmacokinetic parameters.  Here are some  reported ranges: Vd: 0.52 – 0.78 L/kg    Vmax: 6 – 8 mg/kg/day    Km: 5.4 – 6.8 mg/L.  To ensure greater accuracy and appropriateness of dosing, individual determination of Vmax and Km values for each patient based on steady state levels is recommended.

The maintenance dose can then be calculated using the following equation:
MD (mg/day) =  [ ( Vmax x Css) / (S)(F)(Km + Css ]

Vmax   Maximum rate of drug metabolism
Km   Concentration at which the rate of drug metabolism is 50% of Vmax
S  Salt form factor  (use 0.92 for capsules and injection and 1.0 for tablets & elixir)
F  Bioavailability factor (Use 0.95 for oral formulations and 1.0 for intravenous)
Css  Desired concentration at steady state

Other Equations

 

The concentration at steady state can  be estimated using the following equation if Vmax and Km are known (may use population averages if not available):
Css = [Km x (S) x (F) x dose(mg/day)] / [Vmax – (S)(F)(dose(mg/day))].

 

With only one steady state serum level available, you can calculate a value for Vmax if you assume a value for Km (Note: some references assume a value of 4 mg/L for Km)
Vmax = daily dose(mg/day) x (Km/Css + 1)
Derivation of above equation:
(Input  =  Output)
or
Daily dose(mg/day) = [ (Vmax)(Css) / Km + Css]
To simplify further steps, Daily dose will be abbreviated: dd.
dd(Km + Css) = (Vmax)(Css)
dd(Km) + dd(Css) = (Vmax)(Css)
Dividing by Css yields:Vmax = dd + dd(Km)/Css
or
Vmax = daily dose(mg/day) x (Km/Css + 1)
If two steady state serum levels are available, it is possible to derive values for both Vmax and Km.
This is best achieved by the formation of an equation in the form of y = mx + b.  The final equation is:
dd = -Km(dd/Css) + Vmax
(Note: abbreviations are defined above)With  this equation, the y-intercept is equal to Vmax and the slope of the line is equal to (-Km). Remember that the equation for the slope of a line is (y1 – y2) / (x1 –  x2).

The derivation is as follows:
(Input  =  Output)
or
Daily dose(mg/day) = [ (Vmax)(Css) / Km + Css]
To simplify further steps, Daily dose will be abbreviated: dd.
dd(Km + Css) = (Vmax)(Css)
dd(Km) + dd(Css) = (Vmax)(Css)
Dividing by Css yields:dd + (km)(dd)/Css = Vmax and finally,
dd = -Km(dd/Css) + Vmax 
Graphing the values:
Phenytoingraph

It is important to remember that since phenytoin’s elimination is a saturable process, and clearance decreases with increasing concentrations, the steady state concentration is NOT proportional to the maintenance dose (e.g. a non-linear relationship exists). Also, the half-life has little value in estimating the time to steady state.

Additional Info
Note: program uses adjusted body weight for all calculations.  Loading Dose (IV): 10 – 20 mg/kg . Recommended infusion rate for adults: 40-50 mg/min. Elderly (>65): Recommended infusion rate: 20-25 mg/min.  
Oral loading: Give in 3 to 4 divided doses at q2h intervals. (Divided doses increase bioavailability as well as decrease potential for GI side effects such as N&V). The maximum single oral dose should not exceed 400 mg in order to minimize GI side effects and also increase absorption (decrease likelihood of concretions). 
Sampling: 18 to 24 hours after the loading dose, and then every 5 to 7 days to assess trend. 
Average time to steady state: 10-14 days. Half-life: 7 to 42 hours (average = 24 hours).
Conversion to once daily dosing: Consider only after a divided dose regimen on extended phenytoin capsules is established. (Only extended release Dilantin caps are recommended for once daily administration.)  A patient should never receive a once daily dose of elixir or injection as maintenance.
When do you start the maintenance dose? The maintenance dose is started 18-24 hours after the loading dose.
Capsules/injection= 92% phenytoin (sodium salt).    Elixir/tabs=100% phenytoin.  
Equation used to estimate the dose required to increase current level to normal range if subtherapeutic: = [0.7 x IBW x (15 – current level) ] / 0.92* * (if capsules/injection used)
Adjusted phenytoin concentration if low serum albumin = measured total concentration / [ (0.2 x albumin) + 0.1]

Population ranges (another source1): (Vmax:  5.28 to 8.41 mg/kg/day;   Km:  0.83 to 4.18 mg/L;    Vd:  0.74 to 0.97 1/kg)

1. Allen JP, Ludden TM, Burrow SR, Clementi WA, Stavchansky SA.  Phenytoin cumulation kinetics.
Clin Pharmacol Ther. 1979 Oct;26(4):445-8.

Cautions
(1) Always remember that because phenytoin’s elimination is dose-dependent (“capacity limited”), that small increases in dosage can produce disproportionate increases in serum levels (possibly 3 to 4 fold).

(2) Never assume a linear relationship exists between steady state concentrations and the dosage given.

(3) Changes in the daily maintenance dose should be made in small increments (30-100mg maximum). Sample serum levels 7 to 10 days following each dosage change to assess the trend. Steady state is usually achieved after 10-14 days, however, it may be much longer than this in some patients.

(4) Once therapeutic steady state levels are achieved, periodic levels based on clinical judgment should be obtained.  Some studies have found fluctuations in steady state serum concentrations > 150% in patients receiving the same daily maintenance dose. All factors must be considered: addition of interacting drugs, changes in absorption (eg enteral feeding + oral administration of phenytoin), concomitant disease state(s) which may alter phenytoin kinetics, etc.

 (5) Changes in albumin levels or the binding affinity of phenytoin to albumin must be taken into account  (total phenytoin levels are of little value if significant changes occur).  Determination of the free concentration is recommended in these patients with a target concentration of 1-2 mcg/ml.  Factors which may reduce albumin levels include: hepatic cirrhosis, cachexia, burns, malnutrition, and nephrotic syndrome. Factors which may decrease the affinity of phenytoin to albumin or cause displacement include: interacting drugs, increased bilirubin, renal failure …).  The following equations can be used to adjust the serum concentrations based on either reduced albumin levels or presence of renal failure (crcl < 10 ml/min). Some studies have found considerable underestimation of serum levels while using these equations in some patients. Again, the most accurate assessment can be made by obtaining the actual unbound (free) level. The adjustment equations are estimations, and should be considered exactly that.

Hypoproteinemia
(Sheiner-Tozer equation): measured total concentration / [ (0.2 x albumin) + 0.1]
Renal failure:
Cadjusted = Cmeasured / [ (0.1 x albumin) + 0.1) ]

References
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Clin Pharmacol Ther. 1979 Oct;26(4):445-8.
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