++
Because of the large amount of pharmacokinetic variability among
patients, it is likely that doses computed using patient population
characteristics will not always produce phenytoin serum concentrations
that are expected or desirable. Because of pharmacokinetic variability,
the Michaelis-Menten pharmacokinetics followed by the drug, the
narrow therapeutic index of phenytoin, and the desire to avoid adverse
side effects of phenytoin, measurement of phenytoin serum concentrations
is conducted for almost all patients to ensure that therapeutic,
nontoxic levels are present. In addition to phenytoin serum concentrations,
important patient parameters (seizure frequency, potential phenytoin
side effects, etc.) should be followed to confirm that the patient
is responding to treatment and not developing adverse drug reactions.
++
When phenytoin serum concentrations are measured in patients
and a dosage change is necessary, clinicians should seek to use
the simplest, most straightforward method available to determine
a dose that will provide safe and effective treatment. A variety
of methods are used to estimate new maintenance doses or Michaelis-Menten
parameters when one steady-state phenytoin serum concentration is
available. Based on typical Michaelis-Menten parameters, it is possible
to adjust phenytoin doses with one or more steady-state concentrations
using the empiric dosing method. This
is a widely used technique to adjust doses by experienced clinicians.
The Graves-Cloyd method allows adjustment
of phenytoin doses using one steady-state concentration. Because
it uses a power function, it is computationally intensive. The Vozeh-Sheiner method utilizes a specialized
graph and Bayesian pharmacokinetic concepts to individualize phenytoin
doses using a single steady-state concentration. Because of this,
a copy of the graph paper with population orbits must be available,
and plotting the data is time consuming.
++
Sometimes, it is useful to compute phenytoin pharmacokinetic
constants for a patient and base dosage adjustments on these. If
two or more steady-state phenytoin serum concentrations are available
from two or more daily dosage rates, it may be possible to calculate
and use pharmacokinetic parameters to
alter the phenytoin dose. Two graphical methods allow the computation
of Vmax and Km for patients receiving phenytoin,
but they are cumbersome and time consuming. The Mullen
method uses the same specialized graph as the Vozeh-Sheiner
method, but computes the patient’s own Michaelis-Menten parameters
instead of Bayesian pharmacokinetic estimates. The Ludden method uses standard graph paper
to plot the concentration-time data, and Vmax and Km are
computed from the intercept and slope of the resulting line.
++
Finally, computerized methods that incorporate expected population
pharmacokinetic characteristics (Bayesian
pharmacokinetic computer programs) can be used in difficult
cases where serum concentrations are obtained at suboptimal times
or the patient was not at steady state when serum concentrations
were measured. An additional benefit of this method is that a complete
pharmacokinetic workup (Vmax, Km, and V) can be
done with one or more measured concentrations. So that results from
the different methods can be compared, the same cases are used to
compute adjusted doses for phenytoin.
+++
Single Total
Phenytoin Steady-State Serum Concentration Methods
+++
Empiric Dosing
Method
++
Based on the knowledge of population Michaelis-Menten pharmacokinetic
parameters, it is possible to suggest empiric dosage increases for
phenytoin when one steady-state serum concentration is available
(Table 10-4).65 The lower end of the suggested dosage range
for each category tends to produce more conservative increases in steady-state
concentration while the upper end of the suggested dosage range
tends to produce more aggressive increases. These dosage changes
are based on outpatients where avoiding adverse drug reactions is
paramount. For hospitalized patients or patients requiring aggressive
treatment, larger empiric dosage adjustments may be needed. When
dosage increases >100 mg/d are recommended, phenytoin concentrations
and patient response should be carefully monitored.
++
++
Wherever possible, clinicians should avoid using more than one
solid dosage form strength (i.e., mixing 30 mg and 100 mg extended
phenytoin capsules, etc.) for a patient. An effective way to increase
the phenytoin dose for an individual, that requires an increase
in dose of 50 mg/d when using the 100 mg extended phenytoin
sodium capsule dosage form, is to increase the dose by 100 mg every
other day. For example, if a dosage increase of 50 mg/d
is desired for an individual receiving 300 mg/d of extended
phenytoin sodium capsule, a dosage increase of 300 mg/d
alternating with 400 mg/d is possible if the patient is
able to comply with a more complex dosage schedule. Dosage aids
such as calendars, prefilled dosage cassettes, or memory aiding
schemes (400 mg/d on even days, 300 mg/d on odd
days) are all useful in different patient situations. Alternate
daily dosages are possible because of the extended-release characteristics
of extended phenytoin capsules and the long half-life of phenytoin.
++
TD is a 50-year-old, 75-kg (5 ft 10 in) male with simple partial
seizures who requires therapy with oral phenytoin. He has normal
liver and renal function. The patient was prescribed 400 mg/d
of extended phenytoin sodium capsules for 1 month, and the steady-state
phenytoin total concentration equals 6.2 μg/mL.
The patient is assessed to be compliant with his dosage regimen.
Suggest an initial phenytoin dosage regimen designed to achieve
a steady-state phenytoin concentration within the therapeutic range.
++
- 1. Use
Table 10-4 to suggest new phenytoin dose.
- Table 10-4 suggests a dosage increase of ≥100
mg/d for this patient. The dose would be increased to 500
mg/d.
- A steady-state trough total phenytoin serum concentration
should be measured after steady state is attained in 7–14 days.
Phenytoin serum concentrations should also be measured if the patient
experiences an exacerbation of their epilepsy, or if the patient
develops potential signs or symptoms of phenytoin toxicity.
++
GF is a 35-year-old, 55-kg female with tonic-clonic seizures
who requires therapy with oral phenytoin. She has normal liver and
renal function. The patient was prescribed 300 mg/d of
extended phenytoin sodium capsules for 1 month, and the steady-state
phenytoin total concentration equals 10.7 μg/mL.
The patient is assessed to be compliant with her dosage regimen.
Suggest an initial phenytoin dosage regimen designed to achieve
a steady-state phenytoin concentration within the middle of the
therapeutic range.
++
- 1. Use
Table 10-4 to suggest new phenytoin dose.
- Table 10-4 suggests a dosage increase of 50–100 mg/d
for this patient. The dose would be increased to 300 mg/d alternating
with 400 mg/d.
- A steady-state trough total phenytoin serum concentration
should be measured after steady state is attained in 7–14 days.
Phenytoin serum concentrations should also be measured if the patient
experiences an exacerbation of their epilepsy, or if the patient
develops potential signs or symptoms of phenytoin toxicity.
+++
Pseudolinear
Pharmacokinetics Method
++
A simple, easy way to approximate new total serum concentrations
after a dosage adjustment with phenytoin is to temporarily assume
linear pharmacokinetics, then add 15–33% for a
dosage increase or subtract 15–33% for a dosage decrease
to account for Michaelis-Menten pharmacokinetics: Cssnew = (Dnew / Dold)Cssold,
where Cssnew is the expected steady-state concentration
from the new phenytoin dose in μg/mL,
Cssold is the measured steady-state concentration from
the old phenytoin dose in μg/mL, Dnew is
the new phenytoin dose to be prescribed in mg/d, and Dold is
the currently prescribed phenytoin dose in mg/d.66Note: This method is only intended
to provide a rough approximation of the resulting phenytoin steady-state
concentration after an appropriate dosage adjustment, such as that
suggested by the Mauro dosage chart, has been made. The pseudolinear
pharmacokinetics method should never be used to compute a new dose
based on measured and desired phenytoin concentrations.
++
TD is a 50-year-old, 75-kg (5 ft 10 in) male with simple partial
seizures who requires therapy with oral phenytoin. He has normal
liver and renal function. The patient was prescribed 400 mg/d
of extended phenytoin sodium capsules for 1 month, and the steady-state
phenytoin total concentration equals 6.2 μg/mL.
The patient is assessed to be compliant with his dosage regimen.
Suggest an initial phenytoin dosage regimen designed to achieve
a steady-state phenytoin concentration within the therapeutic range.
++
- 1. Use
pseudolinear pharmacokinetics to predict new concentration for a
dosage increase, then compute 15–33% factor to
account for Michaelis-Menten pharmacokinetics.
- Since the patient is receiving extended phenytoin sodium capsules,
a convenient dosage change would be 100 mg/d and an increase
to 500 mg/d is suggested. Using pseudolinear pharmacokinetics,
the resulting total steady-state phenytoin serum concentration would
equal: Cssnew = (Dnew / Dold)Cssold = (500
mg/d / 400 mg/d)6.2 μg/mL = 7.8 μg/mL.
Because of Michaelis-Menten pharmacokinetics, the serum concentration
would be expected to increase 15%, or 1.15 times, to 33%,
or 1.33 times, greater than that predicted by linear pharmacokinetics:
Css = 7.8 μg/mL · 1.15 = 9.0 μg/mL
and Css = 7.8 μg/mL · 1.33 = 10.4 μg/mL.
Thus, a dosage increase of 100 mg/d would be expected to
yield a total phenytoin steady-state serum concentration between
9–10 μg/mL.
- A steady-state trough total phenytoin serum concentration
should be measured after steady state is attained in 7–14 days.
Phenytoin serum concentrations should also be measured if the patient
experiences an exacerbation of their epilepsy, or if the patient
develops potential signs or symptoms of phenytoin toxicity.
++
GF is a 35-year-old, 55-kg female with tonic-clonic seizures
who requires therapy with oral phenytoin. She has normal liver and
renal function. The patient was prescribed 300 mg/d of
extended phenytoin sodium capsules for 1 month, and the steady-state
phenytoin total concentration equals 10.7 μg/mL.
The patient is assessed to be compliant with her dosage regimen.
Suggest an initial phenytoin dosage regimen designed to achieve
a steady-state phenytoin concentration within the middle of the
therapeutic range.
++
- 1.Use
pseudolinear pharmacokinetics to predict new concentration for a
dosage increase, then compute 15–33% factor to
account for Michaelis-Menten pharmacokinetics.
- Since the patient is receiving extended phenytoin sodium capsules,
a convenient dosage change would be 100 mg/d and an increase
to 400 mg/d is suggested. Using pseudolinear pharmacokinetics,
the resulting total steady-state phenytoin serum concentration would
equal: Cssnew = (Dnew / Dold)Cssold = (400
mg/d / 300 mg/d)10.7 μg/mL = 14.3 μg/mL.
Because of Michaelis-Menten pharmacokinetics, the serum concentration
would be expected to increase 15%, or 1.15 times, to 33%,
or 1.33 times, greater than that predicted by linear pharmacokinetics:
Css = 14.3 μg/mL · 1.15 = 16.4 μg/mL
and Css = 14.3 μg/mL · 1.33 = 19.0 μg/mL.
Thus, a dosage increase of 100 mg/d would be expected to
yield a total phenytoin steady-state serum concentration between
16–19 μg/mL.
- A steady-state trough total phenytoin serum concentration
should be measured after steady state is attained in 7–14 days.
Phenytoin serum concentrations should also be measured if the patient
experiences an exacerbation of their epilepsy, or if the patient
develops potential signs or symptoms of phenytoin toxicity.
++
This dosage adjustment method uses a steady-state phenytoin serum
concentration to compute the patient’s own phenytoin clearance
rate (Dold / Cssold, where Dold is
the administered phenytoin dose in mg/d and Cssold is
the resulting measured total phenytoin steady-state concentration
in μg/mL) at the dosage being given, then
uses the measured concentration and desired concentration (Cssnew in μg/mL)
to estimate a new dose (Dnew in mg/d) for the
patient:67 Dnew = (Dold / Cssold) · Cssnew0.199· Cssold0.804.
++
TD is a 50-year-old, 75-kg (5 ft
10 in) male with simple partial seizures who requires therapy with
oral phenytoin. He has normal liver and renal function. The patient
was prescribed 400 mg/d of extended phenytoin sodium capsules
for 1 month, and the steady-state phenytoin total concentration
equals 6.2 μg/mL. The patient is assessed
to be compliant with his dosage regimen. Suggest an initial phenytoin
dosage regimen designed to achieve a steady-state phenytoin concentration
within the therapeutic range.
++
- 1. Use
Graves-Cloyd method to estimate a new phenytoin dose for desired
steady-state concentration.
- Phenytoin sodium 400 mg equals 368 mg of phenytoin (400 mg · 0.92 = 368
mg). A new total phenytoin steady-state serum concentration equal
to 10 μg/mL is chosen for the patient:
Dnew = (Dold / Cssold) · Cssnew0.199· Cssold0.804 = (368
mg/d / 6.2 mg/L) · (10
mg/L)0.199 · (6.2 mg/L)0.804 = 407
mg/d. This is equivalent to 442 mg/d of phenytoin
sodium (407 mg/0.92 = 442 mg) rounded to 450 mg/d,
or 400 mg/d on even days alternating with 500 mg/d
on odd days.
- A steady-state trough total phenytoin serum concentration
should be measured after steady state is attained in 7–14 days.
Phenytoin serum concentrations should also be measured if the patient
experiences an exacerbation of their epilepsy, or if the patient
develops potential signs or symptoms of phenytoin toxicity.
++
GF is a 35-year-old, 55-kg female with tonic-clonic seizures
who requires therapy with oral phenytoin. She has normal liver and
renal function. The patient was prescribed 300 mg/d of
extended phenytoin sodium capsules for 1 month, and the steady-state
phenytoin total concentration equals 10.7 μg/mL.
The patient is assessed to be compliant with her dosage regimen.
Suggest an initial phenytoin dosage regimen designed to achieve
a steady-state phenytoin concentration of 18 μg/mL.
++
- 1. Use
Graves-Cloyd method to estimate a new phenytoin dose for desired
steady-state concentration.
- Phenytoin sodium 300 mg equals 276 mg of phenytoin (300 mg · 0.92 = 276
mg). A new total phenytoin steady-state serum concentration equal
to 18 μg/mL is chosen for the patient:
Dnew = (Dold / Cssold) · Cssnew0.199 · Cssold0.804 = (276
mg/d / 10.7 mg/L) · (18
mg/L)0.199 · (10.7 mg/L)0.804 = 308
mg/d. This is equivalent to 335 mg/d of phenytoin
sodium (308 mg/0.92 = 335 mg) rounded to 350 mg/d,
or 300 mg/d on odd days alternating with 400 mg/d
on even days.
- A steady-state trough total phenytoin serum concentration
should be measured after steady state is attained in 7–14 days.
Phenytoin serum concentrations should also be measured if the patient
experiences an exacerbation of their epilepsy, or if the patient
develops potential signs or symptoms of phenytoin toxicity.
+++
Vozeh-Sheiner
or Orbit Graph Method
++
A graphical method that employs population Michaelis-Menten information
using Bayes’ theorem can also be used to adjust phenytoin
doses using a single steady-state total concentration.68 This
method employs a series of orbs encompassing 50%, 75%,
85%, etc. of the population parameter combinations for
Vmax and Km on the plot suggested by Mullen for
use with multiple steady-state/dosage pairs (Figure 10-3).
The use of the population’s parameter orbs allows the plot
to be used with one phenytoin steady-state concentration/dose
pair.
++
++
The graph is divided into two sectors. On the left side of the
x-axis, a steady-state total phenytoin concentration is plotted.
On the y-axis, the phenytoin dosage rate (in mg/kg/d
of phenytoin; S = 0.92 for phenytoin sodium and fosphenytoin
PE dosage forms) is plotted. A straight line is drawn between these
two points, extended into the right sector, and through the orbs
contained in the right sector. If the line intersects more than
one orb, the innermost orb is selected, and the midpoint of the
line contained within that orb is found and marked with a point.
The midpoint within the orb and the desired steady-state phenytoin
total concentration (on the left portion of the x-axis) are connected
by a straight line. The intersection of this line with the y-axis
is the new phenytoin dose required to achieve the new phenytoin
concentration. If needed, the phenytoin dose is converted to phenytoin
sodium or fosphenytoin amounts. If a line parallel to the y-axis
is drawn down to the x-axis from the midpoint of the line contained
within the orb, an estimate of Km (in μg/mL)
is obtained. Similarly, if a line parallel to the x-axis is drawn
to the left to the y-axis from the midpoint of the line contained
within the orb, an estimate of Vmax (in mg/kg/d)
is obtained.
++
TD is a 50-year-old, 75-kg (5 ft 10 in) male with simple partial
seizures who requires therapy with oral phenytoin. He has normal
liver and renal function. The patient was prescribed 400 mg/d
of extended phenytoin sodium capsules for 1 month, and the steady-state
phenytoin total concentration equals 6.2 μg/mL.
The patient is assessed to be compliant with his dosage regimen.
Suggest an initial phenytoin dosage regimen designed to achieve
a steady-state phenytoin concentration within the therapeutic range.
++
- 1. Use
Vozeh-Sheiner method to estimate a new phenytoin dose for desired
steady-state concentration.
- A new total phenytoin steady-state serum concentration equal
to 10 μg/mL is chosen for the patient.
Using the orbit graph, the serum concentration/dose information
is plotted. (Note: phenytoin dose = 0.92 · phenytoin
sodium dose = 0.92 · 400 mg/d = 368
mg/d; 368 mg/d / 75 kg = 4.9
mg/kg/d; Figure 10-3.) According to the graph,
a dose of 5.5 mg/kg/d of phenytoin is required
to achieve a steady-state concentration equal to 10 μg/mL.
This equals an extended phenytoin sodium capsule dose of 450 mg/d,
administered by alternating 400 mg/d on even days and 500
mg/d on odd days: (5.5 mg/kg/d · 75
kg) / 0.92 = 448 mg/d, rounded to 450
mg/d.
- A steady-state trough total phenytoin serum concentration
should be measured after steady state is attained in 7–14 days.
Phenytoin serum concentrations should also be measured if the patient
experiences an exacerbation of their epilepsy, or if the patient
develops potential signs or symptoms of phenytoin toxicity.
++
GF is a 35-year-old, 55-kg female with tonic-clonic seizures
who requires therapy with oral phenytoin. She has normal liver and
renal function. The patient was prescribed 300 mg/d of
extended phenytoin sodium capsules for 1 month, and the steady-state
phenytoin total concentration equals 10.7 μg/mL.
The patient is assessed to be compliant with her dosage regimen.
Suggest an initial phenytoin dosage regimen designed to achieve
a steady-state phenytoin concentration of 18 μg/mL.
++
- 1. Use
Vozeh-Sheiner method to estimate a new phenytoin dose for desired
steady-state concentration.
- A new total phenytoin steady-state serum concentration equal
to 18 μg/mL is chosen for the patient.
Using the orbit graph, the serum concentration/dose information
is plotted. (Note: phenytoin dose = 0.92 · phenytoin
sodium dose = 0.92 · 300 mg/d = 276
mg/d; 276 mg/d / 55 kg = 5.0
mg/kg/d; Figure 10-4.). According to the graph,
a dose of 5.7 mg/kg/d of phenytoin is required
to achieve a steady-state concentration equal to 18 μg/mL.
This equals an extended phenytoin sodium capsule dose of 350 mg/d,
administered by alternating 300 mg/d on even days and 400
mg/d on odd days: (5.7 mg/kg/d · 55
kg) / 0.92 = 341 mg/d, rounded to 350
mg/d.
- A steady-state trough total phenytoin serum concentration
should be measured after steady state is attained in 7–14 days.
Phenytoin serum concentrations should also be measured if the patient
experiences an exacerbation of their epilepsy, or if the patient
develops potential signs or symptoms of phenytoin toxicity.
++
+++
Two or More
Phenytoin Steady-State Serum Concentrations at Two or More Dosage
Levels Methods
++
In order to utilize each of the dosage schemes in this section,
at least two phenytoin steady-state serum concentrations at different
dosage rates are needed. This requirement can be difficult to achieve.
+++
Empiric Dosing
Method
++
Based on the knowledge of population Michaelis-Menten pharmacokinetic
parameters, it is possible to suggest empiric dosage increases for
phenytoin when there are two or more steady-state serum concentrations
at two or more dosage levels.66 For instance, if a patient
has a steady-state phenytoin concentration equal to 11.2 μg/mL
on 300 mg/d of phenytoin sodium and 25.3 μg/mL
on 400 mg/d of phenytoin sodium, it is obvious that a dose
of 350 mg/d of phenytoin sodium will probably produce a
steady-state phenytoin serum concentration in the mid-to-upper end
of the therapeutic range. Similarly, if a patient has a steady-state
phenytoin concentration equal to 11.2 μg/mL
on 300 mg/d of phenytoin sodium and 15.0 μg/mL
on 400 mg/d of phenytoin sodium, it is apparent that a
dose of 450 mg/d of phenytoin sodium will probably produce
a steady-state phenytoin serum concentration in the upper end of
the therapeutic range. In the latter situation, Table 10-4 can be
useful to suggest dosage increases.
++
TD is a 50-year-old, 75-kg (5 ft 10 in) male with simple partial
seizures who requires therapy with oral phenytoin. He has normal
liver and renal function. The patient was prescribed 400 mg/d
of extended phenytoin sodium capsules for 1 month, and the steady-state
phenytoin total concentration equals 6.2 mg/mL. The dosage
was increased to 500 mg/d of extended phenytoin sodium
capsules for another month, the steady state phenytoin total concentration
equals 22.0 mg/mL, and the patient has some lateral-gaze
nystagmus. The patient is assessed to be compliant with his dosage regimen.
Suggest a new phenytoin dosage regimen designed to achieve a steady-state
phenytoin concentration within the mid-to-upper end of the therapeutic
range.
++
- 1.Empirically
suggest new phenytoin dose.
- The next logical dose to prescribe is phenytoin sodium 450
mg/d to be taken by the patient as 400 mg/d on
even days and 500 mg/d on odd days.
- A steady-state trough total phenytoin serum concentration
should be measured after steady state is attained in 7–14 days.
Phenytoin serum concentrations should also be measured if the patient
experiences an exacerbation of their epilepsy, or if the patient
develops potential signs or symptoms of phenytoin toxicity.
++
GF is a 35-year-old, 55-kg female
with tonic-clonic seizures who requires therapy with oral phenytoin.
She has normal liver and renal function. The patient was prescribed
300 mg/d of extended phenytoin sodium capsules for 1 month,
and the steady-state phenytoin total concentration equals 10.7 μg/mL.
At that time, the dose was increased to 350 mg/d of extended
phenytoin sodium capsules for an additional month, and the resulting
steady state concentration was 15.8 mg/mL. The patient
is assessed to be compliant with her dosage regimen. Suggest a new
phenytoin dosage regimen increase designed to achieve a steady-state
phenytoin concentration within the upper end of the therapeutic
range.
++
- 1.Empirically
suggest new phenytoin dose.
- The next logical dose to prescribe is phenytoin sodium 400
mg/d (Table 10-4).
- A steady-state trough total phenytoin serum concentration
should be measured after steady state is attained in 7–14 days.
Phenytoin serum concentrations should also be measured if the patient
experiences an exacerbation of their epilepsy, or if the patient
develops potential signs or symptoms of phenytoin toxicity.
++
This dosage approach uses the same dose/concentration
plot as that described for the Vozeh-Sheiner or orbit graph method,
but the population orbs denoting the Bayesian distribution of Vmax and
Km parameters are omitted.69,70 As before, the
graph is divided into two sectors. On the left side of the x-axis,
a steady-state total phenytoin concentration is plotted. On the
y-axis, the phenytoin dosage rate (in mg/kg/d
of phenytoin; S = 0.92 for phenytoin sodium and fosphenytoin
PE dosage forms) is plotted. A straight line is drawn between these
two points and extended into the right sector. This process is repeated
for all steady-state dose/concentrations pairs that are
available. The intersection of these lines in the right sector provides
the Michaelis-Menten constant values for the patient. If a line
parallel to the y-axis is drawn down to the x-axis from the intersection
point, Km (in μg/mL) is obtained.
Similarly, if a line parallel to the x-axis is drawn to the left
to the y-axis from the intersection point, an estimate of Vmax (in
mg/kg/d) is obtained. To compute the new phenytoin
dose, the intersection point and the desired steady-state phenytoin
total concentration (on the left portion of the x-axis) are connected
by a straight line. The intersection of this line with the y-axis
is the new phenytoin dose required to achieve the new phenytoin
concentration. If needed, the phenytoin dose is converted to phenytoin
sodium or fosphenytoin amounts.
++
TD is a 50-year-old, 75-kg (5 ft 10 in) male with simple partial
seizures who requires therapy with oral phenytoin. He has normal
liver and renal function. The patient was prescribed 400 mg/d
of extended phenytoin sodium capsules for 1 month, and the steady-state
phenytoin total concentration equals 6.2 μg/mL.
The dosage was increased to 500 mg/d of extended phenytoin
sodium capsules for another month, the steady state phenytoin total
concentration equals 22.0 μg/mL, and the
patient has some lateral-gaze nystagmus. The patient is assessed
to be compliant with his dosage regimen. Suggest a new phenytoin
dosage regimen designed to achieve a steady-state phenytoin concentration
within the therapeutic range.
++
- 1. Use
Mullen method to estimate a new phenytoin dose for desired steady-state
concentration.
- Using the graph, the serum concentration/dose information
is plotted. (Note: phenytoin dose = 0.92 · phenytoin
sodium dose = 0.92 · 400 mg/d = 368
mg/d, 368 mg/d / 75 kg = 4.9
mg/kg/d; phenytoin dose = 0.92 · phenytoin
sodium dose = 0.92 · 500 mg/d = 460
mg/d, 460 mg/d / 75 kg = 6.1
mg/kg/d; Figure 10-5.) According to the graph,
a dose of 5.5 mg/kg/d of phenytoin is required
to achieve a steady-state concentration equal to 11.5 μg/mL.
This equals an extended phenytoin sodium capsule dose of 450 mg/d,
administered by alternating 400 mg/d on even days and 500
mg/d on odd days: (5.5 mg/kg/d · 75
kg) / 0.92 = 448 mg/d, rounded to 450
mg/d. Vmax = 6.8 mg/kg/d
and Km = 2.2 μg/mL for
this patient.
- A steady-state trough total phenytoin serum concentration
should be measured after steady state is attained in 7–14 days.
Phenytoin serum concentrations should also be measured if the patient
experiences an exacerbation of their epilepsy, or if the patient
develops potential signs or symptoms of phenytoin toxicity.
++
++
GF is a 35-year-old, 55-kg female with tonic-clonic seizures
who requires therapy with oral phenytoin. She has normal liver and
renal function. The patient was prescribed 300 mg/d of
extended phenytoin sodium capsules for 1 month, and the steady-state
phenytoin total concentration equals 10.7 μg/mL.
At that time, the dose was increased to 350 mg/d of extended
phenytoin sodium capsules for an additional month, and the resulting
steady state concentration was 15.8 μg/mL.
The patient is assessed to be compliant with her dosage regimen.
Suggest a new phenytoin dosage regimen increase designed to achieve
a steady-state phenytoin concentration within the upper end of the
therapeutic range.
++
- 1.Use
Mullen method to estimate a new phenytoin dose for desired steady-state
concentration.
- Using the graph, the serum concentration/dose information
is plotted. (Note: Phenytoin dose = 0.92 · phenytoin
sodium dose = 0.92 · 300 mg/d = 276
mg/d, 276 mg/d / 55 kg = 5 mg/kg/d;
phenytoin dose = 0.92 · phenytoin sodium
dose = 0.92 · 350 mg/d = 322
mg/d, 322 mg/d / 55 kg = 5.9
mg/kg/d; Figure 10-6.) According to the graph,
a dose of 6.7 mg/kg/d of phenytoin is required
to achieve a steady-state concentration equal to 22 μg/mL.
This equals an extended phenytoin sodium capsule dose of 400 mg/d:
(6.7 mg/kg/d · 55 kg) / 0.92 = 401
mg/d, rounded to 400 mg/d. Vmax = 9.4
mg/kg/d and Km = 9.5 μg/mL
for this patient.
- A steady-state trough total phenytoin serum concentration
should be measured after steady state is attained in 7–14 days.
Phenytoin serum concentrations should also be measured if the patient
experiences an exacerbation of their epilepsy, or if the patient
develops potential signs or symptoms of phenytoin toxicity.
++
++
This method involves the arrangement of the Michaelis-Menten
equation so that two or more maintenance doses (MD, in mg/d
of phenytoin) and steady-state concentrations (Css in mg/L = μg/mL)
can be used to obtain graphical solutions for Vmax and
Km: MD = – Km(MD / Css) + Vmax.31 When
maintenance dose is plotted on the y-axis and MD/Css is
plotted on the x-axis of Cartesian graph paper, a straight line
with a y-intercept of Vmax and a slope equal to – Km is
found. If three or more dose/concentration pairs are available,
it is best to actually plot the data so the best straight line can
be drawn through the points. However, if only two dose/concentration
pairs are available, a direct mathematical solution can be used.
The slope for a simple linear equation is the quotient of the change
in the y-axis values (Δy) and the change in the
x-axis values (Δx): slope = Δy/Δx.
Applying this to the above rearrangement of the Michaels-Menten
equation, –Km = (MD1 – MD2) / [(MD1/Css1) – (MD2 / Css2)],
where the subscript 1 indicates the higher dose and 2 indicates
the lower dose. Once this has been accomplished, Vmax can
be solved for in the rearranged Michaelis-Menten equation: Vmax = MD + Km(MD / Css).
The Michaels-Menten equation can be used to compute steady-state
concentrations for a given dose or vica versa.
++
TD is a 50-year-old, 75-kg (5 ft 10 in) male with simple partial
seizures who requires therapy with oral phenytoin. He has normal
liver and renal function. The patient was prescribed 400 mg/d
of extended phenytoin sodium capsules for 1 month, and the steady-state
phenytoin total concentration equals 6.2 μg/mL.
The dosage was increased to 500 mg/d of extended phenytoin
sodium capsules for another month, the steady state phenytoin total
concentration equals 22.0 μg/mL, and the
patient has some lateral-gaze nystagmus. The patient is assessed
to be compliant with his dosage regimen. Suggest a new phenytoin
dosage regimen designed to achieve a steady-state phenytoin concentration
within the therapeutic range.
++
1.Use Ludden method to estimate Vmax and Km.
++
- Using the graph, the serum concentration/dose
information is plotted. (Note: Phenytoin dose = 0.92 · phenytoin
sodium dose = 0.92 · 400 mg/d = 368
mg/d, 368 mg/d / 75 kg = 4.9
mg/kg/d; phenytoin dose = 0.92 · phenytoin
sodium dose = 0.92 · 500 mg/d = 460
mg/d, 460 mg/d / 75 kg = 6.1
mg/kg/d; Figure 10-7.) According to the graph,
Vmax = 510 mg/d and Km = 2.4
mg/L.
- Because only two dose/steady-state concentrations
pairs are available, a direct mathematical solution can also be
conducted: –Km = (MD1 – MD2) / [(MD1/Css1) – (MD2/Css2)] = (460
mg/d – 368 mg/d) / [(460
mg/d / 22 mg/L) – (368
mg/d / 6.2 mg/L)] = –2.4
mg/L, Km = 2.4 mg/L; Vmax = MD + Km(MD/Css) = 368
mg/d + 2.4(368 mg/d / 6.2 mg/L) = 510
mg/d.
++
++
2. Use
Michaelis-Menten equation to compute a new phenytoin dose for desired
steady-state concentration.
++
- According to the Michaelis-Menten equation, a dose equal
to 450 mg of phenytoin sodium is required to achieve a steady-state
concentration equal to 10.4 μg/mL:
++
++
- This dose would administered by alternating 400 mg/d
on even days and 500 mg/d on odd days.
- A steady-state trough total phenytoin serum concentration
should be measured after steady state is attained in 7–14 days.
Phenytoin serum concentrations should also be measured if the patient
experiences an exacerbation of their epilepsy, or if the patient
develops potential signs or symptoms of phenytoin toxicity.
++
GF is a 35-year-old, 55-kg female
with tonic-clonic seizures who requires therapy with oral phenytoin.
She has normal liver and renal function. The patient was prescribed
300 mg/d of extended phenytoin sodium capsules for 1 month,
and the steady-state phenytoin total concentration equals 10.7 μg/mL.
At that time, the dose was increased to 350 mg/d of extended
phenytoin sodium capsules for an additional month, and the resulting
steady state concentration was 15.8 μg/mL.
The patient is assessed to be compliant with her dosage regimen.
Suggest a new phenytoin dosage regimen increase designed to achieve
a steady-state phenytoin concentration within the upper end of the
therapeutic range.
++
- 1.Use
Ludden method to estimate Vmax and
Km.
- Using the graph, the serum concentration/dose information
is plotted. (Note: Phenytoin dose = 0.92 · phenytoin
sodium dose = 0.92 · 300 mg/d = 276
mg/d, phenytoin dose = 0.92 · phenytoin
sodium dose = 0.92 · 350 mg/d = 322
mg/d; Figure 10-8.) According to the graph, Vmax = 495
mg/d and Km = 8.5 mg/L.
- Because only two dose/steady-state concentrations
pairs are available, a direct mathematical solution can also be
conducted: –Km = (MD1 – MD2) / [(MD1/Css1) – (MD2/Css2)] = (322
mg/d – 276 mg/d) / [(322
mg/d / 15.8 mg/L) – (276
mg/d / 10.7 mg/L)] = – 8.5
mg/L, Km = 8.5 mg/L; Vmax = MD + Km(MD/Css) = 322
mg/d + 8.5 mg/L(322 mg/d / 15.8
mg/L) = 495 mg/d.
- 2. Use
Michaelis-Menten equation to compute a new phenytoin dose for desired
steady-state concentration.
- According to the Michaelis-Menten equation, a dose equal to
400 mg of phenytoin sodium is required to achieve a steady-state
concentration equal to 24.6 μg/mL:
++
++
- A steady-state trough total phenytoin serum concentration
should be measured after steady state is attained in 7–14 days.
Phenytoin serum concentrations should also be measured if the patient
experiences an exacerbation of their epilepsy, or if the patient
develops potential signs or symptoms of phenytoin toxicity.
++