PHENYTOIN

Prepared by:
Ayat Nofal
Jehan Khalil
PRIFE INTRODUCTION
PRIFE INTRODUCTION
 PHENYTOIN is an antiepileptic drug used in the treatment of
epilepsy.

 Administered orally or IV.

PRIFE INTRODUCTION
 Narrow therapeutic window drug

 Protein Binding:
90%-95% protein bound, only unbound fraction is active

 Therapeutic range:
- Total= 10 -20 g/ml
- Free= 1-2 g/ml
PRIFE INTRODUCTION
Dose-related side effects:

Total Phenytoin Conc. Adverse Effect

(g/ml)
20 Nystagmus
30 Ataxia
40 Diminished mental capacity

50 Seizures
PRIFE INTRODUCTION
Not dose-related side effects:

Adverse Effect

Gingival hyperplasia
Hirsutism
Coarsening of facial features
Peripheral neuropathy
DRUG INTERACTIONS
PRIFE INTRODUCTION

 Metabolism:
Hepatic (CYP 2C9 and CYP 2C19)

 Elimination:
Urine
PRIFE INTRODUCTION

Exhibits nonlinear or
Michaelis-Menten kinetics.
Nonlinear (Michaelis-
Menten) Elimination
Michaelis-Menten Parameter

Phenytoin elimination
rate:

C  Vmax
Eliminatio n rate 
Km  C
Michaelis-Menten
Parameter

Drug CL is constantly changing

as the dose changes.

Clearance
CL ↓ as drug conc. ↑

Dose
Michaelis-Menten Parameter

Large interpatient variability:

 Vmax = 100 to 1000 mg/day
 Km = 1 to 15 μg/ml
Michaelis-Menten Parameter

Population Vmax and Km Values

Normal adult with normal liver Vmax= 7 mg/kg/d
and renal function as well as Km= 4 μg/mL
normal plasma protein binding

Younger children (6 months–6 Vmax = 12 mg/kg/d

years) Km = 6 μg/mL

For older children (7–16 years) Vmax = 9 mg/kg/d

Km = 6 μg/mL
Volume of Distribution
Volume of Distribution

 The volume of distribution for patients with normal

phenytoin plasma protein binding is estimated at 0.7 L/kg
for adults.

 For obese individuals 30% or more above their ideal body

weight, the volume of distribution can be estimated using
the following equation:

V = 0.7 L/kg [IBW + 1.33(TBW − IBW)]

Bioavailability
Bioavailability
IV Capsule Susp/Chew Tab
Bioavailability, F 1 1 1

Salt Factor, S 0.92 0.92 1

Prodrug of Phenytoin
FOSPHENYTOIN

 Fosphenytoin (Cerebyx) is a prodrug of Phenytoin that has

no anticonvulsant activity of its own.

 It is rapidly and completely converted to Phenytoin.

 It is well tolerated IV and IM.

FOSPHENYTOIN
 It was developed to avoid local complications of parenteral
administration of Phenytoin.

 After IV Fosphenytoin administration there was a 9%

incidence of pain or burning at the infusion site, compared
with 90% after phenytoin administration.
FOSPHENYTOIN
 Fosphenytoin contains only 66% Phenytoin Sodium and is
correctly prescribed and labeled in units of “PE” meaning
“Phenytoin Sodium equivalents”.

 It contains 150 mg Fosphenytoin per 2ml ampul, providing

100 mg PE (100 mg phenytoin sodium equivalents).
FOSPHENYTOIN
Phenytoin Dose
Determination
 Initial Dose
Determination
Initial Dose Determination
Where,
Vmax is the maximum rate of
Css  Vmax metabolism in mg/day
D S is the fraction of the phenytoin salt
S(Km  Css) form that is active Phenytoin

LD  (Css . V)/S (0.92 for Phenytoin Sodium injection

and capsules; 0.92 for Fosphenytoin
because doses are prescribed as a
Phenytoin Sodium equivalent or PE,
1.0 for Phenytoin acid suspensions
and tablets)
Initial Dose Determination
D is the maintenance dose of the
Phenytoin salt contained in the
dosage form in mg/day
Css  Vmax
D Css is the Phenytoin concentration in
S(Km  Css) mg/L (which equals μg/mL),
Km is the substrate concentration in
LD  (Css . V)/S mg/L (which equals μg/mL) where
the rate of metabolism = Vmax/2,
LD is the loading dose.
Initial Dose Determination
 Intravenous Phenytoin Sodium doses should be short-term
infusions given no greater than 50 mg/min, and
intravenous Fosphenytoin doses should be short-term
infusions given no greater than 150 mg/min PE.

 Css can be drawn within 8-10 days (after the initiation or a

change in the regimen).
Example 1

UO is a 10-year-old, 40-kg male with simple partial seizures

who requires therapy with oral phenytoin. He has a normal
liver and renal function. Suggest an initial phenytoin
suspension dosage regimen designed to achieve a steady-state
phenytoin concentration equal to 12 μg/ml.
The Solution of Example 1

The Vmax for older children (7-16 years) patient is Vmax=9

mg/kg/day and Km= 6 g/ml.

For a 40-kg patient, Vmax= 9*40 = 360 mg/day

For this patient Km= 6 g/ml

= (12*360)/(1*(6+12))= 240 mg/day

 Use of phenytoin serum
concentrations to alter doses
One measurement available
Orbit Graph Approach
Orbit Graph Approach
 This method represents a graphical application of Bayesian
feedback.

 Uses one or more Css at a known dose and allows the

estimation of the most probable Vmax and Km values for
the patient.
Orbit Graph Approach
Advantages of the method:

 Provides relatively accurate estimates of Vmax and Km

 Provides an indication of how "unusual" the patient's

kinetics are compared to the rest of the population.
Orbit Graph Approach
The orbit graph is a plot of
Vmax vs. km with probability
contours drawn on it.
The x-axis is labeled Km and
the extension of the x-axis in
the negative direction is
labeled Css.
The y-axis labeled both
Vmax and dose.
The dose is plotted as
mg/kg/d of Phenytoin.
S=0.92 for Phenytoin sodium
and Fosphenytoin PE dosage
forms.
Orbit Graph Approach
 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.
Orbit Graph Approach
 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.
Orbit Graph Approach
 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.
Orbit Graph Approach
 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.
Orbit graph
Example 2
TD is a 50-year-old, 73.5-kg (5 ft 10 in) male with simple
partial seizures who require therapy with oral phenytoin. He
has a 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 6.0 μg/mL. The patient is assessed to be
compliant with his dosage regimen. Modify Phenytoin sodium
capsules dosage regimen to achieve a steady-state phenytoin
concentration of 10 μg/ml.
 On the left side of the x-axis, a steady-
state observed phenytoin level is plotted
On the y-axis, the phenytoin dosage rate
(in mg/kg/d of phenytoin) 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
phenytoin (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
The intersection of this line with the y-axis is the
new phenytoin dose required to achieve the new
phenytoin concentration
Orbit Graph Approach

According to the graph, a dose of 5.9 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 471

mg/d (5.9 mg/kg/d ⋅ 73.5 kg) / 0.92 = 471 mg/d
Calculate Vmax and Km from the
plot
Calculate the dose from Vmax and Km

= 473 mg/day
 Use of phenytoin serum
concentrations to alter doses
Two measurements available
Orbit Graph Approach
Dosage Adjustment with 2 or more Css Observations

 This method assists in the determination of dosage

adjustments when two or more Css values at different doses
are available.

 This is also a graphical method and the axis used are the
same as for the "orbit graph“ method.
Dosage Adjustment with 2 or more Css Observations

 This method assists in the determination of dosage

adjustments when two or more Css values at different doses
are available.

 This is also a graphical method and the axis used are the
same as for the "orbit graph“ method.
Dosage Adjustment with 2 or more Css
Observations
 With this method, however, the estimate of Vmax and km
is not based on the probability contours but on the
intersection points of the lines for each Css - dose pair.
Example 3
TD is a 50-year-old, 73.5-kg (5 ft 10 in) male with simple
partial seizures who require therapy with oral phenytoin. He
has a 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 6.0 mg/L. 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/L, 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 of 15 mg/L.
 Plot the dosing rate (mg/kg/day) and
observed level for the first dosing rate and
join them by a straight line
Plot the dosing rate (mg/kg/day) and observed
level for the second dosing rate and join them
by a straight line
Identify the intersection of the two lines
Use the intersection to determine new dose:
connect the intersection to the target
concentration
Use the intersection to determine new dose:
connect the intersection to the target
concentration
Use the intersection to determine new dose
Use the intersection to determine Vmax and Km
 Use of phenytoin serum
concentrations to alter doses
Two measurements available
Mathematical equations
Dosage Adjustment with 2 or more Css
Observations (Mathematical equations)

As explained earlier:
Dosage Adjustment with 2 or more Css
Observations (Mathematical equations)
 For the first dosing rate (D1 and S1) and measured level
(Css1):

 For the second dosing rate (D2) and measured level

(Css2):

 You can solve the two equations for Vmax and Km

Example 3
TD is a 50-year-old, 73.5-kg (5 ft 10 in) male with simple
partial seizures who require therapy with oral phenytoin. He
has a 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 6.0 mg/L. 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/L, 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 of 15 mg/L.
The solution of Example 3 (Mathematical equations)

 First dosing rate (D1=400 mg/d, S1=0.92, and Css1= 6

mg/L):

 Second dosing rate (D2=500 mg/d, S2=0.92, and Css2=

22 mg/L):
The solution of Example 3 (Mathematical equations)

 First dosing rate (D1=400 mg/d, S1=0.92, and Css1= 6

mg/L):

 Second dosing rate (D2=500 mg/d, S2=0.92, and Css2=

22 mg/L):
The solution of Example 3 (Mathematical equations)
HYPOALBUMINEMIA
HYPOALBUMINEMIA

 Normal Albumin concentrations of 3.5 - 5 g/dL

 Hypoalbuminemia: Low Albumin concentrations
 Decrease in plasma albumin, will Increase the free
fraction of Phenytoin that is highly bound to albumin
 Binding ratio of Phenytoin is significantly correlated with
albumin levels
 Albumin concentrations below 3 g/dL are associated with
high Phenytoin unbound fractions in the plasma.
HYPOALBUMINEMIA

Albumin Conc. Phenytoin unbound fractions

2.5–3 g/dL 15–20%

2.0–2.5 g/dL >20%

HYPOALBUMINEMIA

 Hypoalbuminemia can be found in patients with:

• Liver disease
• Nephrotic syndrome,
• Pregnant women,
• Cystic fibrosis patients,
• Burn patients,
• Trauma patients,
• Malnourished individuals,
• Elderly.
 Total bilirubin concentrations in excess of 2 mg/dL are
associated with abnormal Phenytoin plasma protein
binding.
 End-stage renal disease patients (creatinine clearance 80–
100 mg/dL) accumulate unidentified compound(s) in their
blood that displace phenytoin from plasma protein binding
sites. Abnormal phenytoin binding persists in these
patients even when dialysis procedures are instituted.
HYPOALBUMINEMIA

 Drugs that are highly bound to albumin and cause plasma

protein binding displacement drug interactions with
Phenytoin include:

• Warfarin,
• Valproic acid,
• Aspirin (>2 g/d),
• Some highly bound nonsteroidal anti-inflammatory agent
CALCULATIONS
CALCULATIONS

Patients with altered Phenytoin plasma protein binding:

 Free fraction (fB) is available
 Unbound phenytoin concentrations are unavailable
FREE FRACTION (fB)
IS AVAILABLE
FREE FRACTION (FB) IS AVAILABLE

Free fraction (fB) is available:

Once the free fraction (fB) has been determined for a patient with
altered Phenytoin plasma protein binding, it is often not necessary
to obtain additional unbound drug concentrations

fB = Cf /C

Where C is the total concentration and Cf is the unbound

concentration
FREE FRACTION (FB) IS AVAILABLE
Situations that caused altered plasma protein binding

Stable (albumin or bilirubin

Variable (the disease state status or
concentration, hepatic or renal function,
drug therapy changes)
other drug doses, etc.)

Total phenytoin concentrations can be New unbound phenytoin fraction will

converted to concurrent unbound be present and need to be remeasured
values and used for therapeutic drug using an unbound/total phenytoin
monitoring purposes. concentration pair
FREE FRACTION (FB) IS AVAILABLE
For example, an end-stage renal failure patient is receiving
phenytoin therapy as well as valproic acid and warfarin.
The measured total and unbound phenytoin concentrations are 5
μg/mL and 1.5 μg/mL, respectively.

Yielding an unbound fraction of 30%.

[fB = Cf /C = (1.5 μg/mL / 5 μg/mL) = 0.30].

The next day, a total phenytoin concentration is measured and

equals 6 μg/mL.
The estimated unbound concentration using this information would
be 1.8 μg/ml.
Cf = fBC = 0.30 ⋅ 6 μg/mL = 1.8 μg/mL
 UNBOUND PHENYTOIN
CONCENTRATIONS ARE UNAVAILABLE
UNBOUND PHENYTOIN CONCENTRATIONS ARE
UNAVAILABLE
The most common surrogate is an estimation of the equivalent total
Phenytoin concentration that would provide the same unbound
Phenytoin concentration if the patient had a normal unbound fraction
value of 10%. These calculations “normalize” the total phenytoin
concentration so that it can be compared to the usual Phenytoin
therapeutic range of 10–20 μg/mL and used for dosage adjustment
purposes.
UNBOUND PHENYTOIN
CONCENTRATIONS ARE UNAVAILABLE
The equation for hypoalbuminemia is

C Normal Binding = C/(X ⋅ Alb + 0.1)

Where C Normal Binding is the normalized total Phenytoin concentration in

μg/mL,
C is the actual measured Phenytoin concentration in μg/mL,
X is a constant equal to 0.2 if protein binding measurements were conducted
at 37°C or 0.25 if conducted at 25°C, and Alb is the albumin concentration
in g/dL. If the patient has end-stage renal disease (creatinine clearance 
10-15 ml/min) constant value (X = 0.1)
UNBOUND PHENYTOIN
CONCENTRATIONS ARE UNAVAILABLE
Because these methods assume that the normal unbound fraction of
phenytoin is 10%, the estimated unbound phenytoin concentration (Cf
EST) is computed using the following formula:

(Cf EST) = 0.1 C Normal Binding

UNBOUND PHENYTOIN
CONCENTRATIONS ARE UNAVAILABLE
A different approach is taken by the equations used for patients with
concurrent valproic acid administration. In this case, the unbound
phenytoin concentration (Cf EST) is estimated using simultaneously
measured total phenytoin (PHT in μg/mL) and valproic acid (VPA in
μg/mL) concentrations:

Cf EST = (0.095 + 0.001 ⋅ VPA) PHT

UNBOUND PHENYTOIN
CONCENTRATIONS ARE UNAVAILABLE
This value is compared to the usual therapeutic range for unbound
Phenytoin concentrations (1–2 μg/mL) and used for dosage adjustment
purposes.

It should be noted that these equations only provide estimates of their

respective concentrations, and actual unbound phenytoin
concentrations should be measured whenever possible in patients with
suspected abnormal Phenytoin plasma protein binding.
EXAMPLE 1

JM is an epileptic patient being treated with Phenytoin. He

has hypoalbuminemia (albumin = 2.2 g/dL) and normal renal
function (creatinine clearance = 90 mL/min). His total
Phenytoin concentration is 7.5 μg/mL. Assuming that any
unbound concentrations performed by the clinical laboratory
will be conducted at 25°C, compute an estimated
normalized Phenytoin concentration for this patient.
EXAMPLE 1
The solution:
 Choose the appropriate equation to estimate normalized total
Phenytoin concentration at the appropriate temperature

C Normal Binding = C/(X ⋅ Alb + 0.1)

X= 0.25 according to the question, the protein binding

measurements conducted at 25°C
C Normal Binding = C/(0.25 ⋅ Alb + 0.1)
= (7.5 μg/mL) / (0.25 ⋅ 2.2 g/dL + 0.1) = 11.5 μg/mL
EXAMPLE 1

Cf EST = 0.1 C Normal Binding

= 0.1 ⋅ 11.5 μg/mL = 1.2 μg/mL

Remember:
• Cf it is the unbound concentration
• Normal unbound fraction value = 10% of normalized total
Phenytoin concentration
EXAMPLE 1

Cf EST = 0.1 C Normal Binding

= 0.1 ⋅ 11.5 μg/mL = 1.2 μg/mL

Remember:
• Cf it is the unbound concentration
• Normal unbound fraction value = 10% of normalized total
Phenytoin concentration
EXAMPLE 1

This patient’s estimated normalized total phenytoin concentration

is expected to provide an unbound concentration equivalent to a
total phenytoin concentration of 11.5 μg/mL for a patient with
normal drug-protein binding (Cf EST = 1.2 μg/mL).

Because the estimated total value is within the therapeutic range

of 10–20 μg/mL, it is likely that the patient has an unbound
Phenytoin concentration within the therapeutic range. If possible,
this should be confirmed by obtaining an actual, measured
unbound Phenytoin concentration
EXAMPLE 2

LM is an epileptic patient being treated with Phenytoin. He has

hypoalbuminemia (albumin = 2.2 g/dL) and poor renal function
(creatinine clearance = 10 mL/min). His total Phenytoin
concentration is 7.5 μg/mL. Compute an estimated normalized
phenytoin concentration for this patient
EXAMPLE 2
The solution:
Choose the appropriate equation to estimate the normalized total
phenytoin concentration

C Normal Binding = C/(X ⋅ Alb + 0.1)

X= 0.1 according to the question, the patient has a poor renal

function (creatinine clearance = 10 mL/min)
C Normal Binding = C/(0.1 ⋅ Alb + 0.1)
= (7.5 μg/mL) / (0.1 ⋅ 2.2 g/dL + 0.1) = 23.4 μg/mL
EXAMPLE 2

Cf EST = 0.1 C Normal Binding

= 0.1 ⋅ 23.4 μg/mL = 2.3 μg/mL

Remember:
• Cf it is the unbound concentration
• Normal unbound fraction value = 10% of normalized total
Phenytoin concentration
EXAMPLE 2

This patient’s estimated normalized total phenytoin

concentration is expected to provide an unbound concentration
equivalent to a total phenytoin concentration of 23.4 μg/mL for
a patient with normal drug-protein binding (Cf EST = 2.3 μg/mL).

Because the estimated total value is above the therapeutic range

of 10–20 μg/mL, it is likely that the patient has an unbound
Phenytoin concentration above the therapeutic range. If
possible, this should be confirmed by obtaining an actual,
measured unbound phenytoin concentration.
EXAMPLE 3

PM is an epileptic patient being treated with Phenytoin and

Valproic acid. He has a normal albumin concentration (albumin =
4.2 g/dL) and normal renal function (creatinine clearance = 90
mL/min). His steady-state total Phenytoin and Valproic acid
concentrations are 7.5 μg/mL and 100 μg/mL, respectively.
Compute an estimated unbound phenytoin concentration for this
patient.
EXAMPLE 2
The solution:
Choose an appropriate equation to estimate unbound phenytoin
concentration.

Cf EST = (0.095 + 0.001 ⋅ VPA) PHT

= (0.095 + 0.001 ⋅ 100 μg/mL)7.5 μg/mL = 1.5 μg/mL

EXAMPLE 3

This patient’s estimated unbound phenytoin concentration is

expected to be within the therapeutic range for unbound
concentrations. If possible, this should be confirmed by obtaining
an actual, measured unbound phenytoin concentration
 EFFECTS OF DISEASE STATES AND
CONDITIONS ON PHARMACOKINETICS
AND DOSING
EFFECTS OF DISEASE STATES AND CONDITIONS
ON PHARMACOKINETICS AND DOSING

 10- to 15-fold variation in Michaelis-Menten pharmacokinetic

parameters which creates a huge amount of variability in dose
requirements.
 An individualized dosage regimen for each patient prescribed
Phenytoin must be determined to accomplish therapeutic
goals.
EFFECTS OF DISEASE STATES AND CONDITIONS
ON PHARMACOKINETICS AND DOSING

 Unfortunately, measurement of Vmax and Km for Phenytoin is

very difficult to accomplish for research or clinical purposes.
Because of this, the effects of disease states and conditions on
these parameters are largely unknown.
EFFECTS OF DISEASE STATES AND CONDITIONS
ON PHARMACOKINETICS AND DOSING

Patients with liver cirrhosis or acute hepatitis:

 Have reduced Phenytoin clearance because of the destruction
of liver parenchyma. This loss of functional hepatic cells
reduces the amount of CYP2C9 and CYP2C19 available to
metabolize the drug and decreases Vmax.

 The volume of distribution is larger because of reduced plasma

protein binding. Protein binding is reduced and the unbound
fraction is increased due to hypoalbuminemia and/or
hyperbilirubinemia (especially albumin ≤3 g/dL and/or total
bilirubin ≥2 mg/dL).
EFFECTS OF DISEASE STATES AND CONDITIONS
ON PHARMACOKINETICS AND DOSING

 The effects that liver disease has on Phenytoin

pharmacokinetics are highly variable and difficult to accurately
predict.

 It is possible for a patient with liver disease to have relatively

normal or grossly abnormal Phenytoin clearance and volume of
distribution.
 For example, a liver disease patient who has relatively normal
albumin and bilirubin concentrations can have a normal
volume of distribution for Phenytoin.
EFFECTS OF DISEASE STATES AND CONDITIONS
ON PHARMACOKINETICS AND DOSING

 An index of liver dysfunction can be gained by applying the

Child-Pugh clinical classification system to the patient.

 A Child-Pugh score greater than 8 is grounds for a decrease of

25–50% in the initial daily drug dose for Phenytoin.
EFFECTS OF DISEASE STATES AND CONDITIONS
ON PHARMACOKINETICS AND DOSING

 As in any patient with or without liver dysfunction, initial doses

are meant as starting points for dosage titration based on
patient response and avoidance of adverse effects.

 Phenytoin serum concentrations and the presence of adverse

drug effects should be monitored frequently in patients with
liver cirrhosis.
EFFECTS OF DISEASE STATES AND CONDITIONS
ON PHARMACOKINETICS AND DOSING

 For patients who are prone to hypoalbuminemia,

unbound phenytoin concentration monitoring
should be considered in these patients especially
when Albumin concentrations are ≤3 g/Dl.
 High bilirubin concentrations can also be found in
patients with biliary tract obstruction or hemolysis.
Unbound phenytoin concentration monitoring
should be considered in these patients especially
when total bilirubin concentrations are ≥2 mg/dL.
Thank you …