Download Anticonvulsant Pharmacokinetics

Anticonvulsant
Pharmacokinetics
Dennis Mungall, Pharm.D.
Director, Virtual Education, NTPD
Associate Professor Pharmacy
Practice
Ohio State University
College of Pharmacy
Absorption of Phenytoin

Phenytoin sodium is 92% phenytoin
 The time to peak is 3-12 hours after single
dose of a capsule or tablet
 Dilantin Kapseals are the only formulation
that has absorption characteristics necessary
for once daily dosing
 Oral absorption fo Dilantin approaches
100%
Oral preparations of Phenytoin
Time to Peak Cp

Dose (mg)
 400
 800
 1600

Peak Time ( hrs)
 8.4
 13.2
 31.5
Parenteral Administration of
Phenytoin
Gugler R et al . Clin Pharmac.Ther 1976; 135-42
Distribution 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
protein 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
concentration for Albumin

Cnormal = Cobserved/(0.2*alb+0.1)
Metabolism

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
Dose/cp
Lund L. Bilogical Effects of Drugs. University Park Press
1972;227-39
Demonstration of Dose/CP
nonlinearity for Phenytoin
Richens A., Dunlop A. Lancet 1975;2:247-48
Steady 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
Phenytoin
Time to steady state based on
dosing rate
Time to 90% of SS as a
function of Vmax and Km
Equation for Time to 90% SS
 T90%
=(Km*Vd)/(Vm-Dose) *
(2.3*Vm –0.9*Dose)
Conditions Affection Phenytoin
Vmax increased
Condition or
Example
Disease
Enzyme induction Concurrent
phenobarb/Carbaz
epine
Vmax decreased
Cirrhosis
Decreased
enzyme activity
Km increased
Competitive
Inhibition
Decrease
ProteinBinding
Cimetidine or
Chloramphenicol
Km decreased
Dec. albumin or
displacers:Valproi
c acid
Clinical Response and Side
Effects
Kutt H et al. Arch Neurol 1964; 11:642-48
Estimating the Loading Dose
of 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 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
Based on one SS Phenytoin CP
Vozeh S et al . J Pharmacokinet Biopharm 1981;9:131-46
Estimation of Dose based on two SS
Phenytoin CP:Mullen Method
Mullen RW. Clin Pharm Ther 1978;23:228-32
Estimation of Dose based on two SS
Phenytoin CP:Ludden Method
Ludden TM et al . Clin Pharm Ther 1977;21:287-93
Case 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 his
Chest 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: 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 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
Method
Dose
Cp
Dose/CP
Ludden Example

Y intercept=1225mg/day= Vmax
 Slope=11.6mg/l= Km
 Dose/day=Vmax xCp/Km+cp
 Dose/day=1225x15/11.6+15
 Dose/day= 690mg phenytoin acid
 Dose/day=750 mg phenytoin sodium
Case 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
name/age
After inputing the name and age click on accept
Choose phenytoin
Select Edit Demographics
Enter in the height , weight,
serum albumin and serum
creatinine
When completed , click on accept
Select inpatient dosing
Insert 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 :
Select Parameters
Review the Vmax, Km, Vd
Click on done when finished
Predicting 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