Anticonvulsant Anticonvulsant PharmacokineticsPharmacokinetics

Dennis Mungall, Pharm.D.

Director, Virtual Education, NTPD

Associate Professor Pharmacy Practice

Ohio State University

College of Pharmacy

Absorption of PhenytoinAbsorption of Phenytoin

Phenytoin sodium is 92% phenytoinThe time to peak is 3-12 hours after single

dose of a capsule or tabletDilantin Kapseals are the only formulation

that has absorption characteristics necessary for once daily dosing

Oral absorption fo Dilantin approaches 100%

Oral preparations of PhenytoinOral preparations of Phenytoin

Time to Peak CpTime to Peak Cp

Dose (mg) 400 800 1600

Peak Time ( hrs) 8.4 13.2 31.5

Parenteral Administration of Parenteral Administration of PhenytoinPhenytoin

Gugler R et al . Clin Pharmac.Ther 1976; 135-42

Distribution of PhenytoinDistribution of Phenytoin

Following IV phenytoin distribution to tissues occurs in 30-60 minutes

Distribution to the brain is very rapid The mean volume of distribution is comparable to

total body water: 0.6-0.7 Liters/kg. Phenytoin binds primarily to albumin, with

approximately 10 percent of the drug normally unbound.

Conditions that lead to decreased Conditions that lead to decreased protein binding of Phenytoinprotein binding of Phenytoin

Decreased In serum Albumin

Burns Hepatic cirrhosis Nephrotic syndrome Pregnancy Cystic Fibrosis

Decreased in affinity of binding to albumin

Renal Failure Jaundice Other medications

Adjustment of Total Phenytoin Adjustment of Total Phenytoin concentration for Albumin concentration for Albumin

Cnormal = Cobserved/(0.2*alb+0.1)

MetabolismMetabolism

Elimination of phenytoin occurs primarily by biotransformation to inactive hydroxylated metabolites.

The process of phenytoin elimination is saturable

Thus , increases in dose lead to disproportionate increases in phenytoin concentration

Variation in Phenytoin Variation in Phenytoin Dose/cpDose/cp

Lund L. Bilogical Effects of Drugs. University Park Press1972;227-39

Demonstration of Dose/CP Demonstration of Dose/CP nonlinearity for Phenytoinnonlinearity for Phenytoin

Richens A., Dunlop A. Lancet 1975;2:247-48

Steady State ConcentrationSteady State Concentration

Vmax= maximum rate of phenytoin metabolism in mg/day

Km: the concentration at which the rate

of metabolism is half maximal ( mg/liter

Css= Km-Dose(day)/Vmax-Dose(day)

Saturation Pathway for Saturation Pathway for PhenytoinPhenytoin

Time to steady state based on Time to steady state based on dosing ratedosing rate

Time to 90% of SS as a Time to 90% of SS as a function of Vmax and Kmfunction of Vmax and Km

Equation for Time to 90% SSEquation for Time to 90% SS

T90% =(Km*Vd)/(Vm-Dose) *

(2.3*Vm –0.9*Dose)

Conditions Affection PhenytoinConditions Affection PhenytoinCondition or Disease

Example

Vmax increased Enzyme induction Concurrent phenobarb/Carbazepine

Vmax decreased Cirrhosis Decreased enzyme activity

Km increased Competitive Inhibition

Cimetidine or Chloramphenicol

Km decreased Decrease ProteinBinding

Dec. albumin or displacers:Valproic acid

Clinical Response and Side Clinical Response and Side EffectsEffects

Kutt H et al. Arch Neurol 1964; 11:642-48

Estimating the Loading Dose Estimating the Loading Dose of Phenytoinof Phenytoin

LD= Vd (C desired – C observed)/S*F Where:

Vd = volume of distribution ( 0.65L/kg)

S=salt factor ( 0.92)

F= fraction absorbed ( 1 )

Cdesired=10 to 20 mg/L

Cobserved: if the patient is on phenytoin

already and has a level prior to therapy

Estimating Maintenance DoseEstimating Maintenance Dose

Mean Km for adults: 5.8 mg/L ( 0.1-27) and

5.3 mg/l for children

Mean Vmax for adults:8mg/kg/day, children 12 mg/kg/day

Dose/day= Vmax*Css/Km+Css

Estimating Maintenance Dose Estimating Maintenance Dose Based on one SS Phenytoin CPBased on one SS Phenytoin CP

Vozeh S et al . J Pharmacokinet Biopharm 1981;9:131-46

Estimation of Dose based on two SS Estimation of Dose based on two SS Phenytoin CP:Mullen MethodPhenytoin CP:Mullen Method

Mullen RW. Clin Pharm Ther 1978;23:228-32

Estimation of Dose based on two SS Estimation of Dose based on two SS Phenytoin CP:Ludden MethodPhenytoin CP:Ludden Method

Ludden TM et al . Clin Pharm Ther 1977;21:287-93

Case Study #1Case Study #1

Mr SG is a 58 y/o, 72 inch, 70 kg male, seen recently with symptoms of a lower Respiratory infection. At this time he had a lesion noted on hisChest X-ray. A lung biopsy revealed a carcinoma with metastasis to The head , demonstrated via a CT scan. His albumin was 4 gm/l and serum creatinine 1.0 .Phenytoin therapy was initiated prohylactically at a dosage of 400 mg daily. Two weeksLater the patient had a grand mal seizure and the phenytoin Cp was5 mg/l. The dosage was increased to 500 mg qd and 3 weeks laterThe phenytoin concentration was 7 mg/l.

Case # 1: QuestionsCase # 1: Questions

Using the Ludden method graph and estimate the Vmax and Km for this patient.

Using this information , estimate a dose necessary to achieve a phenytoin concentration of 15 mg/l

Given the Vmax and Km estimate the timeto 90% of steady state

Estimate a Loading dose to achieve 15mg/l

now.

Case 1: Using DrugCalcCase 1: Using DrugCalc

Using drugcalc, input the patient history , dosing history, and phenytoin history and model this

See how Vmax and Km compare with the Ludden method.

Case 1 : Answers to Ludden Case 1 : Answers to Ludden MethodMethod

Dose Cp Dose/CP

400x0.92=

368mg

5 mg/l 73.6 l/day

500x0.92=

460mg

7mg/l 65.7 l/day

Ludden ExampleLudden Example

Y intercept=1225mg/day= VmaxSlope=11.6mg/l= KmDose/day=Vmax xCp/Km+cpDose/day=1225x15/11.6+15Dose/day= 690mg phenytoin acidDose/day=750 mg phenytoin sodium

Case 1 : Using DrugcalcCase 1 : Using Drugcalc

Input the patient dosage/cp history and estimate Vmax and Km

Using the Dosage calculator, estimate

the dose to achieve a phenytoin concentration of 15 mg/L

Screen # 1 : Input the Screen # 1 : Input the name/agename/age

After inputing the name and age click on accept

Choose phenytoin Choose phenytoin

Select Edit DemographicsSelect Edit Demographics

Enter in the height , weight, Enter in the height , weight, serum albumin and serum serum albumin and serum

creatininecreatinine

When completed , click on accept

Select inpatient dosingSelect inpatient dosing

Insert Dose/Cp historyInsert Dose/Cp history

Using the shortcut for multiple doses, 14s indicating 2 weeks , 21 s Indicating 3 weeks. D is for data ( concentration) . ( s for sustained release) Click on add after entering each line. When complete click on accept

Choose Predict to Model : Choose Predict to Model : Select ParametersSelect Parameters

Review the Vmax, Km, VdReview the Vmax, Km, Vd

Click on done when finished

Predicting SS dosePredicting SS dose

Using the new vmax and Km and the equation for dose, reestimate, by hand the dose of phenytoin necessary to achieve a ss concentration of 15 mg/l

To Predict Dose, Select To Predict Dose, Select Predict and then Steady StatePredict and then Steady State

Predicting SS dosePredicting SS dose