Transcript Total Phenytoin Conc (μg/ml)

Anticonvulsants: Phenytoin
Phenytoin
• Anticonvulsant used for
many seizure disorders.
• Administered po or iv.
• Exhibits nonlinear or
Michaelis-Menten
kinetics.
• 90% protein bound, only
unbound fraction is
active
• Therapeutic range:
– Total = 10-20 μg/ml
– Free = 1-2 μg/ml
Total
Phenytoin
Adverse Effect
Conc (μg/ml)
>15
Drowsiness or fatigue
>20
Nystagmus
>30
>40
>50
Ataxia, slurred speech, &
Incoordination
Mental status changes: ↓
mentation, severe confusion or
lethargy & coma
Drug-induced seizures
Phenytoin: Nonlinear (MichaelisMenten) elimination
• Phenytoin elimination rate:
C  Vmax
Eliminatio n rate 
Km  C
Phenytoin
– Vmax = 100 to 1000 mg/day
– Km = 1 to 15 μg/ml
• V = 0.65 L/kg
Clearance
• Metabolized by hepatic cytochrome P450.
• Both CYP 2C9 and CYP 2C19.
• Drug CL is constantly changing as dose
changes.
• CL ↓ as drug conc. ↑
• Large interpatient variability:
Dose
Michaelis-Menten parameters
• Normal adults with normal liver and renal
function as well as normal plasma protein
binding have an average phenytoin Vmax
of 7 mg/kg/d and Km of 4 μg/mL.
• Michaelis-Menten parameters for younger
children (6 months–6 years) are Vmax =
12 mg/kg/d and Km = 6 μg/mL
• For older children (7–16 years) Vmax = 9
mg/kg/d and Km = 6 μg/mL
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)]
Other parameters
• Extended phenytoin capsule dosage form
has good bioavailability (F = 1)
Fosphenytoin
• Fosphenytoin (Cerebyx) has no anticonvulsant
activity of its own, is a prodrug of phenytoin.
• It was developed to avoid local complications of
parenteral administration of phenytoin.
• It is rapidly and completely converted to
phenytoin.
• After IV fosphenytoin administration there was a
9% incidence of pain or burning at the infusion
site, compared with 90% after phenytoin
administration.
• It is well tolerated IV and IM.
Fosphenytoin
• Fosphenytoin contains only 66%
phenytoin free acid and is correctly
prescribed and labeled in units of “PE,”
meaning “phenytoin sodium equivalents.”
• It is packaged to be very similar to
phenytoin sodium injection.
• It contains 150 mg fosphenytoin per 2ml
ampul, providing 100 mg PE (100 mg
phenytoin sodium equivalents).
Initial dose determination
Css  Vmax
MD 
S(Km  Css)
LD  (Css . V)/S
where Vmax is the maximum rate of metabolism in
mg/day, S is the fraction of the phenytoin salt form that
is active phenytoin (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), MD is the
maintenance dose of the phenytoin salt contained in the
dosage form in mg/d, Css is the phenytoin concentration
in mg/L (which equals μg/mL), and Km is the substrate
concentration in 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.
Example 1
• 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. Suggest
an initial phenytoin dosage regimen
designed to achieve a steady-state
phenytoin concentration equal to 12
μg/mL.
Example 1
• The Vmax for a nonobese adult patient
with normal liver and renal function is 7
mg/kg/d.
• For a 75-kg patient, Vmax = 525 mg/day
• For this individual, Km = 4 mg/L.
Css  Vmax
12  525
MD 

 428 mg/d,
S(Km  Css) 0.92(4  12)
rounded to 400 mg/d
When do you recommend that a
Css be drawn?
• The time required for 90% of Css to be
reached:
Km(V)
2.3Vmax  0.9  Xd ,
t 90% 
2
Vmax  Xd 
where Xd is the daily dose
Use of phenytoin serum
concentrations to alter doses
Orbit Graph Approach for Adjusting
Phenytoin Dosage
• This method represents a graphical application
of Bayesian feedback.
• Uses one or more Css at a known dose & allows
the estimation of the most probable Vmax and
Km value for the patient.
• 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
• The orbit graph is a plot of Vmax
vs. km with probability contours
drawn on it.
• x-axis is labeled Km & the
extension of the x-axis in the
negative direction labeled Css.
• The y-axis labeled both Vmax
and dose.
• Dose is plotted as mg/kg/d of
phenytoin.
• S=0.92 for phenytoin sodium
and fosphenytoin PE dosage
forms.
Orbit graph
1. On the left side of the x-axis, a steady-state total
phenytoin concentration is plotted.
2. 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.
3. A straight line is drawn between these two points,
extended into the right sector, and through the orbs
contained in the right sector.
4. 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.
5. The midpoint within the orb and the desired steadystate phenytoin total concentration (on the left
portion of the x-axis) are connected by a straight
line.
Orbit graph
6. The intersection of this line with the y-axis is the new
phenytoin dose required to achieve the new
phenytoin concentration.
7. If needed, the phenytoin dose is converted to
phenytoin sodium or fosphenytoin amounts.
8. If a line parallel to the y-axis is drawn down to the xaxis from the midpoint of the line contained within
the orb, an estimate of Km (in μg/mL) is obtained.
9. 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.
Example 2
• 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.
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
Example 2
• 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.
Example 2
• Calculate:
– Km
– Vmax
Dosage Adjustment with 2 or
More Css Observations (Orbit method)
• This method assists in determination of dosage
adjustments when two or more Css values at
different doses are available.
• This is also a graphical method & the axis used
are the same as for the "orbit graph“ method.
• 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
Dosage Adjustment with 2 or
More Css Observations (Orbit method)
Dosage Adjustment with 2 or
More Css Observations (Mathematical
equations)
• At steady state input= output
FD Vmax  Css
K0 

τ
Km  Css
• Administer the drug at two different rates
and then determine Css at each of the two
administrations:
K 0 (1) Km  K 0 (1)Css(1)  Vmax  Css (1)
K 0 ( 2 ) Km  K 0 ( 2 )Css( 2 )  Vmax  Css (2)
Example 3
• RM is a 32 year old, 80kg male who is being seen in the
Neurology Clinic. Prior to his last visit he had been taking
300mg of Phenytoin daily; however, because his
seizures were poorly controlled and because his plasma
concentration was only 8mg/L, his dose was increased
to 350mg daily. Now he complains of minor CNS side
effects and his reported plasma Phenytoin concentration
is 20mg/L. Renal and hepatic function are normal.
Assume that both of the reported plasma concentrations
represent steady state and that the patient has compiled
with the prescribed dosing regimens. Calculate RM’s
apparent Vm and Km and a new daily dose of Phenytoin
that will result in a steady state level of about 15mg/L.
K 0 (1)  300 mg / day, CSS (1)  8 mg / L
K 0 (2)  350 mg / day, CSS (2)  20 mg / L
K 0 (1) * Km  K 0 (1) * CSS (1)  Vm * CSS (1)
K 0 (2) * Km  K 0 (2) * CSS (2)  Vm * CSS (2)
300 * Km  300 * 8  Vm * 8  37.5 * Km  300  Vm (1)
  
350 * Km  350 * 20  Vm * 20  17.5 * Km  350  Vm (2)
Eqn (1)- Eqn(2):
20 * Km  50  0
50
Km 
 2.5 mg / L
20
Eqn (1):
Vm  37.5 * Km  300  37.5 * 2.5  300  393.75 mg / day