Phenytoin dosing guidelines
by D.McAuley, GlobalRPh Inc.
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:
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
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
1. Allen JP, Ludden TM, Burrow SR, Clementi WA,
Stavchansky SA. Phenytoin cumulation kinetics.
Clin Pharmacol Ther. 1979 Oct;26(4):445-8.
2. Bachmann KA, Belloto RJ Jr. Differential kinetics of
phenytoin in elderly patients. Drugs Aging. 1999
Sep;15(3):235-50.
3. Bauer LA, Blouin RA. Age and phenytoin kinetics in
adult epileptics. Clin Pharmacol Ther. 1982
Mar;31(3):301-4.
4. Burton ME, Vasko MR, Brater DC. Comparison of
drug dosing methods. Clin Pharmacokinet. 1985 JanFeb;10(1):1-37.
5. Dager WE, Inciardi JF, Howe TL. Estimating
phenytoin concentrations by the Sheiner-Tozer method
in adults with pronounced hypoalbuminemia. Ann
Pharmacother. 1995 Jul-Aug;29(7-8):667-70.
6. Dasgupta A, Dennen DA, Dean R, McLawhon RW.
Prediction of free phenytoin levels based on [total
phenytoin]/[albumin] ratios. Potential errors with
hypoalbuminemia. Am J Clin Pathol. 1991
Feb;95(2):253-6.
7. Dela Cruz FG, Kanter MZ, Fischer JH, Leikin JB.
Efficacy of individualized phenytoin sodium loading
doses administered by intravenous infusion. Clin
Pharm. 1988 Mar;7(3):219-24.
8. Flint N, Lopez LM, Robinson JD, Williams C, Salem
RB. Related ArticlesComparison of eight phenytoin
dosing methods in institutionalized patients.
Ther Drug Monit. 1985;7(1):74-80.
9. Grasela TH, Sheiner LB, Rambeck B, Boenigk HE,
Dunlop A, Mullen PW, Wadsworth J, Richens A,
Ishizaki T, Chiba K, et al. Steady-state
pharmacokinetics of phenytoin from routinely collected
patient data
10. Gugler R, Manion CV, Azarnoff DL. Phenytoin:
pharmacokinetics and bioavailability. Clin Pharmacol
Ther. 1976 Feb;19(2):135-42.
11. Hayes MJ, Langman MJ, Short AH. Changes in
drug metabolism with increasing age: 2. phenytoin
clearance and protein binding. Br J Clin Pharmacol.
1975 Feb;2(1):73-9.
12. Hudson SA, Farquhar DL, Thompson D, Smith
RG. Phenytoin dosage individualization--five methods
compared in the elderly. J Clin Pharm Ther. 1990
Feb;15(1):25-34.
13. Liponi DF, Winter ME, Tozer TN. Renal function
and therapeutic concentrations of phenytoin. Neurology.
1984 Mar;34(3):395-7.
14. Mabuchi H, Nakahashi H. A major inhibitor of
phenytoin binding to serum protein in uremia. Nephron.
1988;48(4): 310-4.
15. Martin E, Tozer TN, Sheiner LB, Riegelman S. The
clinical pharmacokinetics of phenytoin. J Pharmacokinet
Biopharm. 1977 Dec;5(6):579-96.
16. Martin E, Gambertoglio JG, Adler DS, Tozer TN,
Roman LA, Grausz H. Removal of phenytoin by
hemodialysis in uremic patients. JAMA. 1977 Oct
17;238(16):1750-3.
17. Mason GD, Winter ME. Appropriateness of
sampling times for therapeutic drug monitoring. Am J
Hosp Pharm. 1984 Sep;41(9):1796-801.
18. Mauro LS, Mauro VF, Bachmann KA, Higgins JT.
Accuracy of two equations in determining normalized
phenytoin concentrations. DICP. 1989 Jan;23(1):64-8.
19. McCauley DL, Tozer TN, Winter ME. Time for
phenytoin concentration to peak: consequences of firstorder and zero-order absorption. Ther Drug Monit. 1989
Sep;11(5):540-2.
20. Mlynarek ME, Peterson EL, Zarowitz BJ.
Predicting unbound phenytoin concentrations in the
critically ill neurosurgical patient. Ann Pharmacother.
1996 Mar;30(3): 219-23.
21. Peterson GM, Khoo BH, von Witt RJ. Clinical
response in epilepsy in relation to total and free serum
levels of phenytoin. Ther Drug Monit. 1991
Sep;13(5):415-9.
22. Pryka RD, Rodvold KA, Erdman SM. An updated
comparison of drug dosing methods. Part I: Phenytoin.
Clin Pharmacokinet. 1991 Mar;20(3):209-17.
23. Sawchuk RJ, Rector TS. Steady-state plasma
concentrations as a function of the absorption rate and
dosing interval for drugs exhibiting concentrationdependent clearance: consequences for phenytoin
therapy. J Pharmacokinet Biopharm. 1979
Dec;7(6):543-55.
24. Sheiner LB, Beal SL. Evaluation of methods for
estimating population pharmacokinetics parameters. I.
Michaelis-Menten model: routine clinical
pharmacokinetic data. J Pharmacokinet Biopharm.
1980 Dec;8(6):553-71.
25. Tozer TN, Winter ME. Phenytoin. In: Evans WE,
Schentag JJ, Jusko WJ, eds. Applied
Pharmacokinetics: Principles of Therapeutic Drug
Monitoring. 3rd Ed. Vancouver, WA: Applied
Therapeutics; 1992: 25.1 - 25.44