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

Ataxia, slurred speech, & Incoordination >40 Total Phenytoin Conc (μg/ml) Adverse Effect >15 Drowsiness or fatigue >20 Nystagmus >30 Ataxia, slurred speech, & Incoordination >40 Mental status changes: ↓ mentation, severe confusion or lethargy & coma >50 Drug-induced seizures

Phenytoin: Nonlinear (Michaelis-Menten) elimination Phenytoin elimination rate:

Phenytoin 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: Vmax = 100 to 1000 mg/day Km = 1 to 15 μg/ml V = 0.65 L/kg Clearance 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 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.

When do you recommend that a Css be drawn? The time required for 90% of Css to be reached:

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 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.

Orbit graph 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.

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 Administer the drug at two different rates and then determine Css at each of the two administrations:

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.

Eqn (1)- Eqn(2): Eqn (1):