Phenytoin (Dilantin) dosing information by D.McAuley

Phenytoin dosing guidelines

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 = 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 ]

V_max	Maximum rate of drug metabolism
K_m	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)
C_ss	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):

C_ss = [K_m x (S) x (F) x dose(mg/day)] / [V_max - (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)

V_max = daily dose(mg/day) x (K_m/C_ss + 1)
Derivation of above equation:
(Input = Output)
or
Daily dose(mg/day) = [ (V_max)(C_ss) / K_m + C_ss]
To simplify further steps, Daily dose will be abbreviated: dd.
dd(K_m + C_ss) = (V_max)(C_ss)
dd(K_m) + dd(C_ss) = (V_max)(C_ss)
Dividing by C_ss yields:

V_max = dd + dd(K_m)/C_ss
or
V_max = daily dose(mg/day) x (K_m/C_ss + 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 = -K_m(dd/C_ss) + V_max
(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) = [ (V_max)(C_ss) / K_m + C_ss]
To simplify further steps, Daily dose will be abbreviated: dd.
dd(K_m + C_ss) = (V_max)(C_ss)
dd(K_m) + dd(C_ss) = (V_max)(C_ss)
Dividing by C_ss yields:

dd + (km)(dd)/Css = Vmax and finally,
dd = -K_m(dd/C_ss) + V_max

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 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

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 Jan-Feb;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 first-order 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 concentration-dependent 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

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