Anticonvulsant Pharmacokinetics

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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 - PowerPoint PPT Presentation

Transcript of Anticonvulsant Pharmacokinetics

  • Anticonvulsant PharmacokineticsDennis Mungall, Pharm.D.Director, Virtual Education, NTPDAssociate Professor Pharmacy PracticeOhio State UniversityCollege of Pharmacy

  • Absorption of PhenytoinPhenytoin 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 dosingOral absorption fo Dilantin approaches 100%

  • Oral preparations of Phenytoin

  • Time to Peak CpDose (mg)4008001600

    Peak Time ( hrs)8.413.231.5

  • Parenteral Administration of PhenytoinGugler R et al . Clin Pharmac.Ther 1976; 135-42

  • Distribution of PhenytoinFollowing IV phenytoin distribution to tissues occurs in 30-60 minutesDistribution to the brain is very rapidThe 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 PhenytoinDecreased In serum AlbuminBurnsHepatic cirrhosisNephrotic syndromePregnancyCystic FibrosisDecreased in affinity of binding to albuminRenal FailureJaundiceOther medications

  • Adjustment of Total Phenytoin concentration for Albumin Cnormal = Cobserved/(0.2*alb+0.1)

  • MetabolismElimination of phenytoin occurs primarily by biotransformation to inactive hydroxylated metabolites. The process of phenytoin elimination is saturableThus , increases in dose lead to disproportionate increases in phenytoin concentration

  • Variation in Phenytoin Dose/cpLund L. Bilogical Effects of Drugs. University Park Press1972;227-39

  • Demonstration of Dose/CP nonlinearity for PhenytoinRichens A., Dunlop A. Lancet 1975;2:247-48

  • Steady State ConcentrationVmax= 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% SST90% =(Km*Vd)/(Vm-Dose) * (2.3*Vm 0.9*Dose)

  • Conditions Affection Phenytoin

  • Clinical Response and Side EffectsKutt H et al. Arch Neurol 1964; 11:642-48

  • Estimating the Loading Dose of PhenytoinLD= Vd (C desired C observed)/S*FWhere: 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 DoseMean 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 CPVozeh S et al . J Pharmacokinet Biopharm 1981;9:131-46

  • Estimation of Dose based on two SS Phenytoin CP:Mullen MethodMullen RW. Clin Pharm Ther 1978;23:228-32

  • Estimation of Dose based on two SS Phenytoin CP:Ludden MethodLudden TM et al . Clin Pharm Ther 1977;21:287-93

  • Case Study #1Mr 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: QuestionsUsing 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/lGiven the Vmax and Km estimate the timeto 90% of steady stateEstimate a Loading dose to achieve 15mg/l now.

  • Case 1: Using DrugCalcUsing 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

  • Ludden ExampleY 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 DrugcalcInput the patient dosage/cp history and estimate Vmax and KmUsing the Dosage calculator, estimate the dose to achieve a phenytoin concentration of 15 mg/L

  • Screen # 1 : Input the name/ageAfter inputing the name and age click on accept

  • Choose phenytoin

  • Select Edit Demographics

  • Enter in the height , weight, serum albumin and serum creatinineWhen completed , click on accept

  • Select inpatient dosing

  • Insert Dose/Cp historyUsing 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, VdClick on done when finished

  • Predicting SS doseUsing 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 Predict and then Steady State

  • Predicting SS dose

  • The greatly increased time to peak is secondary to the low solubility of phenytoin . Cases of severe diarrhea, malabsorption syndromes, or gastric resection, could lead to decreased bioavailability. The absorption of phenytoin is impaired in patients receiving nasogastric feedings. This may be secondary to direct protein binding to the feeding or rapid gastrointestinal transit secondary to the feeding. Intramuscular administration should be avoided because phenytoin precipitates at the site of injection. Absorption post IM administration is erratic and slow. The above figure shows prolonged plasma cp after IM phenytoin compared to intravenous administration. In conditions where albumin is lower than normal the free fraction of phenytoin increases. Thus for any total level of phenytoin , more free would be available to act. The target concentration for phenytoin is 10-20 mg/l under normal circumstances.