Anticonvulsant Pharmacokinetics Dennis Mungall Pharm D Director Virtual

Anticonvulsant Pharmacokinetics Dennis Mungall, Pharm. D. Director, Virtual Education, NTPD Associate Professor Pharmacy Practice Ohio State University College of Pharmacy

Absorption of Phenytoin l Phenytoin sodium is 92% phenytoin l The time to peak is 3 -12 hours after single dose of a capsule or tablet l Dilantin Kapseals are the only formulation that has absorption characteristics necessary for once daily dosing l Oral absorption fo Dilantin approaches 100%

Oral preparations of Phenytoin

Time to Peak Cp Dose (mg) l 400 l 800 l 1600 l Peak Time ( hrs) l 8. 4 l 13. 2 l 31. 5 l

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 l Distribution to the brain is very rapid l The mean volume of distribution is comparable to total body water: 0. 6 -0. 7 Liters/kg. l Phenytoin binds primarily to albumin, with approximately 10 percent of the drug normally unbound. l

Conditions that lead to decreased protein binding of Phenytoin l Decreased l l l In serum Albumin l Burns Hepatic cirrhosis Nephrotic syndrome Pregnancy Cystic Fibrosis l Decreased in affinity of binding to albumin Renal Failure l Jaundice l Other medications

Adjustment of Total Phenytoin concentration for Albumin l Cnormal = Cobserved/(0. 2*alb+0. 1)

Metabolism l Elimination of phenytoin occurs primarily by biotransformation to inactive hydroxylated metabolites. l The process of phenytoin elimination is saturable l 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 l Vmax= maximum rate of phenytoin metabolism in mg/day l 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 l T 90% =(Km*Vd)/(Vm-Dose) * (2. 3*Vm – 0. 9*Dose)

Conditions Affection Phenytoin Vmax increased Vmax decreased Km increased Km decreased Condition or Example Disease Enzyme induction Concurrent phenobarb/Carbaz epine Cirrhosis Decreased enzyme activity Cimetidine or Competitive Chloramphenicol Inhibition Decrease Dec. albumin or Protein. Binding 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 l Where: Vd = volume of distribution ( 0. 65 L/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 l

Estimating Maintenance Dose l Mean Km for adults: 5. 8 mg/L ( 0. 1 -27) and 5. 3 mg/l for children Mean Vmax for adults: 8 mg/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 weeks. Later the patient had a grand mal seizure and the phenytoin Cp was 5 mg/l. The dosage was increased to 500 mg qd and 3 weeks later. The phenytoin concentration was 7 mg/l.

Case # 1: Questions Using the Ludden method graph and estimate the Vmax and Km for this patient. l Using this information , estimate a dose necessary to achieve a phenytoin concentration of 15 mg/l l Given the Vmax and Km estimate the timeto 90% of steady state l Estimate a Loading dose to achieve 15 mg/l now. l

Case 1: Using Drug. Calc l Using drugcalc, input the patient history , dosing history, and phenytoin history and model this l See how Vmax and Km compare with the Ludden method.

Case 1 : Answers to Ludden Method Dose Cp Dose/CP

Ludden Example l. Y intercept=1225 mg/day= Vmax l Slope=11. 6 mg/l= Km l Dose/day=Vmax x. Cp/Km+cp l Dose/day=1225 x 15/11. 6+15 l Dose/day= 690 mg phenytoin acid l Dose/day=750 mg phenytoin sodium

Case 1 : Using Drugcalc l Input the patient dosage/cp history and estimate Vmax and Km l 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, 14 s 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 l 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