Phenytoin Dosing

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PHENYTOIN PHARMACOKINETIC

Do not follow the first-order elimination (Clearance and half-life are not useful).
Undergo Michaelis-Menten (nonlinear) kinetics (using parameters Vmax, Km, Vd.)
When drug metabolism by liver enzymes is saturated, a dose increase can cause the plasma concentration to increase disproportionately (this can happen at therapeutic concentrations.)
Clearance is not constant, so it is not helpful in estimating the time to reach steady state (Vmax and Km are used instead.)
90% protein bound (low albumin level increases the fraction of free/active phenytoin.)
Therapeutic range: 10-20mg/L (total); 1-2mg/L (free);
Population estimate values:
- Vd = 0.7 L/kg (Volume of Distribution)
- Vmax = 7mg/kg/day (Maximum rate of drug metabolism)
- Km = 4mg/L (Michaelis-Menten constant)
Phenytoin is available in two different forms: phenytoin acid (chewable tablets and suspension) and phenytoin sodium (capsules and injectables). Phenytoin sodium is 92% phenytoin acid, so make dose adjustment accordingly for their different bioavailability fractions (F=1 for phenytoin acid and F=0.92 for phenytoin sodium).

PHENYTOIN PHARMACOKINETIC IS DIFICULT TO PREDICT AND NOT AS ACCURATE AS DRUGS FOLLOWING FIRST-ORDER/LINEAR ELIMINATION. USE CLINICAL JUDGMENT AND TREAT THE PATIENT, NOT THE NUMBERS.

Now you want to do:

Calculate a Loading Dose (LD);
Calculate a daily Maintenance Dose (MD);
Adjust daily MD with one known concentration to attain a new desired concentration;
Adjust daily MD from with two reliable concentrations resulted from two different daily dosings;
Calculate additional dose to attain a desired concentration;
Estimate the time to reach (90%) steady-state plasma concentrtion;
Calculate Volume of distribution in patients with abnormal Albumin level;

Calculate Loading Dose (LD):

Vd = 0.7 L/kg

Enter patient's weight: kg

Enter a desired conc. (Css): mg/L

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LD = Vd x Css

LD = mg

Calculate daily Maintenance Dose (MD):

Vmax = 7 mg/kg/day

Km = 4mg/L

Enter patient's weight: kg

Enter a desired conc. (Css): mg/L

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MD = (Vmax x Css) / (Km + Css)

MD = mg

Adjust daily MD with one known concentration to attain a new desired concentration:

Km = 4mg/L

Enter patient's weight: kg

Enter the current MD (cMD): mg

Enter a measured conc.(mCss): mg/L

Enter a desired conc. (dCss): mg/L

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Step 1: Calculate a new Vmax (nVmax)

nVmax = cMD (Km + mCss) / mCss

nVmax = mg/kg/day

Step 2: Calculate a new MD (nMD) by using new Vmax

nMD = (nVmax x dCss) / (Km + dCss)

nMD = mg

Adjust daily MD from with two reliable concentrations resulted from two different daily dosings:

Enter patient's weight: kg

Enter 1st MD: mg

Enter 2nd MD : mg

Enter 1st reported conc. (C1) = mg/L

Enter 2nd reported conc. (C2) = mg/L

Enter a new desired conc. (Css) = mg/L

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Step 1: Calculate new Km (nKm)

nKm = - {(MD1 - MD2) / [(MD1/C1) - (MD2/C2)]}

nKm = mg/L

Step 2: Calculate new Vmax (nVmax) by using new Km (nKm)

nVmax = MD1 (nKm + C1) / C1 or MD2 (nKm + C2) / C2

nVmax = mg/kg/day (using MD1 & C1)

Step 3: Calculate new MD (nMD) by using new Km (nKm) and new Vmax (nVmax)

nMD = (nVmax x Css) / (nKm + Css)

nMD = mg

Calculate additional dose (aLD) to attain a desired concentration:

Vd = 0.7 L/kg

Enter patient's weight: kg

Enter a measured conc. (mCss) = mg/L

Enter a desired conc. (dCss) = mg/L

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aLD = Vd x (dCss - mCss)

aLD = mg

Estimate the time to reach (90%) steady-state plasma concentrtion:

Vd = 0.7 L/kg

Km = 4 mg/L

Vmax = 7 mg/kg/day

Enter patient's weight: kg

Enter daily MD: mg

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t90 = [(Km x Vd) / (Vmax - MD)²] x [(2.3 x Vmax) - (0.9 x MD)]

t90 = days

Calculate Volume of distribution in patients with abnormal Albumin level:

Enter patient's weight: kg

Enter Albumin level:

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Vd = (2.8 / Alb) x Wt

Vd = Liters