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This document Copyright © 2004  D.McAuley, GlobalRPh Inc. All Rights Reserved.

Phenytoin dosing guidelines 
by D.McAuley, GlobalRPh Inc.

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 = C_reported /(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) =  [ ( V_max x C_ss) / (S)(F)(K_m + C_ss ]

Other Equations

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 Information

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:
C_adjusted = C_measured / [ (0.1 x albumin) + 0.1) ]

References