Juntip Kanjanasilp Faculty of Pharmacy Mahasarakham University 11 August 2008

1. Juntip Kanjanasilp Faculty of Pharmacy Mahasarakham University 11 August 2008

2. Nonlinear pharmacokinetics Capacity-limited kinetics (saturation kinetics) First-order kinetics + Zero-order kinetics Prolong elimination half-life ?????????? steady state ??????????????????????? ??????????????????????????????????????? ??????????????????????? enzyme ???? carrier ???????? ??????????????? ???????? metabolites ?????????????

3. Example Absorption Saturable transport Intestinal metabolism Distribution Plasma protein binding CSF transport Tissue binding Cellular Uptake Hepatic uptake Penicillin,riboflavin Prodrugs, salicylamide Ceftriaxone, prednisolone Benzyl penicillins Prednisolone Methicillin Indocyanine green

4. Example (continue) Metabolism Saturable metabolism Co-substrate depletion plasma protein binding Phenytoin Acetaminophen Prednisolone

5. Example (continue) Elimination Glomerular filtration Tubular secretion Tubular reabsorption Biliary secretion Biliary recycling Response Saturable receptor binding Naproxen Mezlocillin,PAH Riboflavin Idiopamide Cimetidine, isotretinoin Phenytoin

7. Michaelis-Menten Equation

10. At Steady-state

13. Objectives Pharmacokinetic parameters of phenytoin Factors that affect to phenytoin concentration and clinical response Applied the pharmacokinetic parameter to adjust dosage regimen Identified DRPs and applied the pharmacokinetic and pharmacodynamic principle to resolve and prevent DRPs

15. Phenytoin 300 mg/d

16. Absorption weak acid (pKa 8.3) Less Water Soluble Mostly absorp at duodenum Saturation Peak/ loading dose

17. Absorption Salt form: phenytoin Na (S =0.92), phenytoic acid (S =1) Dosage form Prompt-release preparation: chewable tablet, suspension (phenytoic acid) Extended release preparation: capsule (phenytoin Na) Injection (phenytoin Na)

18. Absorption Brand/bioavailability Diseases: diarrhea, malabsorption syndrome NG tube feeding IV: propylene glycol, alcohol, sodium hydroxide NSS Rate not more than 50 mg/min cardiovascular collapse/central nervous system depression IM: precipitate

19. Distribution Vd 0.6-0.8 L/kg (0.65 L/kg) protein binding 90-95% Fraction unbound 0.1 Albumin decrease in newborn, elderly, renal/liver disease, burns, injury, pregnancy

23. Metabolism/Elimination metabolize 95% --> inactive metabolites [ 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH)] low extraction drug arene oxidase enzyme: rate limiting step renal 5% CL , t1/2 dependent concentration

25. PHARMACOKINETIC PARAMETER MEC Potential toxic conc. Bioavailable fraction Total body clearance Michalelis constant (Km) Vmax 10 mg/L 20 mg/L 0.85-0.95 22 � 0.2 mL/h/kg 4 mg/L (1-15 mg/L) 7 mg/kg/d (1.4-14 mg/kg/d)

26. PHARMACOKINETIC PARAMETER Children < 6y Vmax (mg/kg/d) > children 7-16 and adult children 6 mo � 6 y Vmax 10 -13 mg/kg/d children 7 � 16 y Vmax 8-10 mg/kg/d Children: Km 2-3 mcg/mL (others 6-8 mcg/mL)

27. PHARMACOKINETIC PARAMETER Race (Genetic) Europe(70 kg): Vmax 415 mg/d Km 5.7 mg/L Japan Km < Europe 23%

28. Km, Vmax and condition or diseases

29. PHARMACOKINETIC PARAMETER (cont.) Half life Vd Unbound percentage in serum Time to steady state Time to peak conc. Percent excreted renally 7-42 h. 0.6-0.8 L/kg 10% (5%-31%) 7-10 d 4-7 h. <5%

30. PHARMACOKINETIC PARAMETER (cont.) Percent removed from the body during hemodialysis (6h) Active metabolites 4% None

31. Adverse drug reactions Acute Toxicity > 20 mg/L Nystagmus > 30 mg/L Ataxia > 40 mg/L Lethargy, Confusion, Coma

32. Adverse drug reactions Chronic Side Effects Gingival hyperplasia Hirsutism Megaloblastic anemia Osteomalacia Peripheral neuropathy

33. Adverse drug reactions Idiosyncratic reactions Skin rashes Steven Johnson syndrome pseudolymphoma Bone marrow suppression Lupuslike reaction Hepatitis Fetal phenytoin syndrome

34. Drug-drug Interaction Absorption: Ca, Mg, Al, sucralfate, activated charcoal --> phenytoin Distribution: salicylates, valproic acid, phenylbutazone Metabolism: carbamazepine, rifampicin, cimetidine, chloramphenicol, ketoconazole Enzyme inducer: folic acid, quinidine, OCs

35. Correction factor Carbamazepine 0.87 Carbamazepine+Phenobarbital 0.80 Chloramphenicol 3.91 Cimetidine 3.91 Folic acid 0.73 Phenobarbital 0.94 Salicylate 0.84 Valproic acid 0.75 (5-10 wk) 0.93 (>6 mo)

36. Dose(adjusted) = Dose(observed)/Q Cp of (phenytoin + drug) = (Cp of phenytoin) x Q

37. Disease-drug Interaction CRF Liver disease Burn Protein malnutrition pregnancy fever head trauma

38. Therapeutic Drug Monitoring Therapeutic range Total drug 10-20 mg/L Free drug 1-2 mg/L Sampling Time Loading dose: after dose 24 h. Maintenance dose: 7 d , q 2-4 wk Sample collection: trough concentration

39. RESAMPLING GUIDELINE Change Dose Rapid Metabolism, Noncompliance Drug Interaction Toxicity Renal or Liver Disease Pregnancy Change Bioavailability Laboratory Error

40. Overdose or Poisoning After suspection of toxicity q 12-24 h. until serum conc. < 20 mg/L

41. Loading dose Status epilepticus: 18-20 mg/kg IV infusion baseline : 15-18 mg/kg IV or oral IV NSS (conc. 5 mg/mL) drip over 1-2 hr Rate < 50 mg/min. hypotension, arrhythmia: PPG, alc, NaOH Oral : divided dose

42. Loading Dose

43. Dosage Adjustment Correction Albumin Hypoalbuminemia less protein binding ----> free fraction 1.1 Normal renal function

44. Dosage Adjustment 1.2 End stage renal disease

45. Dosage Adjustment Normal Albumin /Corrected Albumin 2.1 Two non-steady state levels (Mass-Balance Approach)

46. Dosage Adjustment Vmax (Km= 4 mg/L)

47. Dosage Adjustment

49. Dosage Adjustment 2.2 One steady state concentration calculation

51. Dosage Adjustment 2.3 Two or more steady state concentration calculation cal. Km + Vmax (individual) cal. Dose, Css Orbit graph

53. Time to reach steady state

54. Km, Vmax and t90%

56. References ?????? ????????. 2543. ??????????????????????? Phenytoin. ?????????????????????????????? Therapeutic Drug Monitoring. ?? ?????? ??????????????? ???????? ??????????. ????????????? 1. ?????????????????????? ?????????????? ?????????????????? ???????: ???? 135-159. Michael E. Winter. (1994). Phenytoin. In Mary Anne Koda-Kimble (Ed.), Basic Clinical Pharmacokinetics. (pp.312-348), USA : Applied Therapeutics, Inc. Michael E. Winter and Thomas N. Tozer. Phenytoin.in Gibalcli and Prescott (Ed.), Hanbook of Clinical Pharmacokinetics. (pp.493-539).

58. Male 70 kg cal. loading dose to achieve plasma concentration of 20 mg/L Vd = 0.65 L/kg S = 0.92 F = 1.0 Loading dose = (Vd)(Cp)/(S)(F)

59. Male 70 kg required to increase plasma concentration from 8 to 15 mg/L Loading dose? Vd = 0.65 L/kg

60. Male 37 y/o, 70 kg : 300 mg /d of phenytoin--> 8 mg/L What dose will achieve a steady state conc. of 15 mg/L ? Find Vmax Find Dose If 400 mg/d --> 20 mg/L What dose will achieve a steady state conc. of 15 mg/L ?

61. Male 47 y/o, 60 kg with glomerulonephritis. Creatinine clearance is good. Serum albumin 2.0 g/dL. Receiving phenytoin 300 mg/d and has steady state conc. of 6 mg/L. What would his phenytoin conc. if his albumin normal? If 300 mg/d --> conc. 4 mg/L. What dose is appropriate?

62. Male 59 y/o, 80 kg Phenytoin 300 mg/d ? 8 mg/L (seizure poorly control) phenytoin 350 mg/d ? 20 mg/L (minor CNS ADR) Assume steady state Renal and hepatic are normal What time to reduce conc. 20 mg/L --> 15 mg/L ? What time to reduce conc. 25 mg/L --> 15 mg/L ?

63. Vm =326 mg/d, Km=2.5 mg/L

64. Female 25 y/o, 40 kg Phenytoin 350 mg/d 30 days ? 35 mg/L (ataxia, weakness) Assume steady state Renal and hepatic are normal What time to reduce conc. 35 mg/L --> 15 mg/L ?

65. Male 40 y/o, 80 kg Phenytoin 300 mg/d 21 days Phenytoin level 14 mg/L Is it a represent of steady-state concentration?

67. Male 66 y/o, 60 kg Poor seizure control ? admit OPD: phenytoin 350 mg/d ? 3 mg/L Noncompliance? IPD: phenytoin Na 350 mg/d 5 days ? 18 mg/L Has steady state been achieved?

68. Female 52 y/o, 60 kg Loading dose 1000 mg ? Maintenance dose 300 mg/d 8 days ? phenytoin level 11 mg/L Should her dose be adjusted at this time to achieve the desired phenytoin concentration of 10 to 20 mg/L?

70. Female 56 y/o, 60 kg CRF and seizure disorder Hemodialysis treatment 3 times/week Serum albumin 3.3 g/dL Phenytoin 300 mg/d Steady state 5 mg/L Should her daily phenytoin dose be increased?

71. NG tube feeding Male 35 y/o,55 kg head injury, receive phenytoin 300 mg/d , 7 d later --> conc. 2.1 mg/L. What happened?

72. Guidelines Concentrations ? 7 mg/L ? increase 100 mg dose Concentrations 7-12 mg/L ? increase 50 mg dose Concentrations ? 12 mg/L ? increase 30 mg dose