Myrna Y. Munar, Pharm.D., BCPS

Transcription

1 Phenytoin PK Myrna Y. Munar, Pharm.D., BCPS Associate Professor

2 Clickers Turn clicker on by pressing down menu button Enter you OSU student ID number The up/down diagonal arrows button on the left is the button to SEND your answers The menu button is also used to turn your clicker off But don t turn it off now Raise your hand if you re having trouble OK, let s begin

3 Objectives Upon completion of the required readings and at the end of the scheduled discussion, the Pharm.D. student should be able to: Design an appropriate phenytoin LD and initial MD regimen for a patient Determine the circumstances for which free (unbound) phenytoin levels should be drawn in lieu of or in addition to total (bound and unbound) levels Interpret phenytoin serum levels in relation to patient status (effectiveness, toxicity, protein binding, renal or hepatic function) Calculate PK parameters and formulate changes if necessary based upon patient info, desired therapeutic goals, and phenytoin concentration data

4 Oral Bioavailability (F) F

5 Dilantin Products Phenytoin Acid Dilantin-125 Suspension Phenytoin oral suspension 8 oz bottle, 125 mg phenytoin acid/5 ml Orange-vanilla flavor Store at room temperature S 1.0

6 Dilantin Products Phenytoin Acid Chewable Convenient pediatric dosage form 50 mg phenytoin acid S 1.0

7 Phenytoin sodium 92% phenytoin S 0.92

8 Dilantin Products Phenytoin Sodium Extended phenytoin sodium capsules 30 mg 100 mg FDA has cautioned use of any product other than Dilantin Kapseals for once-aday use S 0.92

9 Parenteral Products Phenytoin Sodium Dilantin IV 50 mg/ml Phenytoin sodium Rate of administration not to exceed 50 mg/min; 25 mg/min in elderly patients or patients with cardiac disease S

10 Parenteral Products Phenytoin Sodium Fosphenytoin (Cerebyx) Always prescribe in phenytoin sodium equivalents! 75 mg/ml fosphenytoin 50mg/mlof phenytoin sodium equivalents 2 ml per vial: 150 mg 100 mg of phenytoin sodium equivalents 10 ml per vial: 750 mg 500 mg of phenytoin sodium equivalents Rate of administration not to exceed 150 mg phenytoin sodium equivalents/min

11 Generic Product The Mylan Brand Extended Phenytoin Sodium The only AB-rated, product that can be substituted for Dilantin Kapseals AB rating: Actual or potential bioequivalence problems have been resolved with adequate in vitro or in vivo evidence supporting bioequivalence. 100 mg, 200 mg, 300 mg capsules S 0.92

12 Bioavailability il problems with generic product...

13 Effect of Food: Dilantin Kapseals vs Mylan Product N 24 healthy volunteers Non blinded, single-dose, randomized, two-period, two-way crossover study 8-hour overnight fast Dilantin or Mylan in random order at 2- week intervals Both products administered with a high-fat breakfast Wilder BJ et al. Neurology 2001;57(4):582-9

14 Effect of Food: Substituting Mylan Product for Dilantin Kapseals Open circle: Mylan AUC 29.4 mgxhr/l Solid circle: Dilantin AUC 33.9 mgxhr/l What is the relative F of Mylan:Dilantin? ya a

15 Relative Bioavailability ( AUC / Dose ) A ( AUC / Dose) F A / F ( / )B B

16 Relative Bioavailability F F A B ( AUC / Dose) ( AUC / Dose) ( 29.4mg hr / L /100mg) ( 33.9mg hr / L /100mg) % reduction in the amount of phenytoin sodium absorbed when Mylan product taken w/food is substituted for Dilantin 95%CI %; 4% does not include 100%, therefore efo e statistically significant A B

17 Conversely...

18 Effect of Food: Substituting Dilantin Kapseals for Mylan Product SAME DATA: Open circle: Mylan AUC 29.4 mgxhr/l Solid circle: Dilantin AUC 33.9 mgxhr/l What is the relative F of Dilantin:Mylan?

19 Relative Bioavailability ( AUC / Dose ) A ( AUC / Dose) F A / F ( / )B B

20 Relative Bioavailability F F ( AUC / Dose) A ( AUC / Dose) B ( 33.9 mg hr / L /100mg ) ( 29.4mg hr / L /100mg) A B % increase in the amount of phenytoin sodium absorbed when Dilantin taken w/food is substituted for Mylan product 95%CI %; does not include 100%, 95%CI %; does not include 100%, therefore statistically significant

21 Translate information to predicted steadystate plasma [phenytoin] A: Dilantin to Mylan 13% decrease in F predicted to result in median 37% decrease in plasma [phenytoin] B: Mylan to Dilantin 15% increase in F predicted to result in 102% increase in median plasma [phenytoin]

22 What is your advice?

23 Mephenytoin (Mesantoin) This is an entirely different drug! Therapeutic range is different PK mcg/ml Rapidly absorbed with C peak within 1 hour Parent drug t 1/ hrs Active major metabolite t 1/ / hours Less extensive protein binding 60% free, unbound

24 Mephenytoin (Mesantoin) ADRs (vs phenytoin) Lower incidence of gingival hyperplasia, ataxia, hirsutism, gastric upset Greater risk of serious side effects: blood dyscrasias, serious dermatologic reactions, SLE, & hepatotoxicity

25 Phenytoin PK

26 What do I do first? Determine loading dose Determine maintenance dose

27 Loading Dose Patients not already receiving phenytoin Patients already receiving phenytoin Based on patient s total body weight In obese (adult) patients, use adjusted d body weight (ABW) IBW + [1.33 (TBW IBW)]

28 Patients not already receiving phenytoin IV loading 2 methods: mg/kg x TBW or ABW (kg) LD (V D ) (C target ) / (S) (F)

29 Calculate an IV LD For a 65 kg nonobese patient

30 IV LD For a 65 kg nonobese patient 15 mg/kg x 65 kg 975 mg phenytoin sodium IV Let s choose 1000 mg phenytoin sodium IV

31 Parenteral Products Phenytoin Sodium Dilantin IV 50 mg/ml Phenytoin sodium 2 ml sterile syringe 2 ml & 5 ml sterile vials

32 IV Admixture How many 5 ml vials would you use for the 1000 mg IV phenytoin sodium loading dose in this patient? Dilantin IV phenytoin sodium 50 Dilantin IV phenytoin sodium 50 mg/ml

33 1000 mg phenytoin sodium/50 mg/ml 20 ml 4 x 5 ml vials 20 ml

34 Phenytoin IV Dilution prior to IV administration Use ml of 0.9% saline or Lactated Ringer s Do not use D5W, insoluble & precipitates! Infuse thru an in-line filter fl (eg 0.22 micron filter) Infusion rate not to exceed 50 mg/min; 25 mg/min in elderly patients or patients with cardiac disease

35 What is the minimum i infusion i time for this patient?

36 1000 mg/50 mg/min 20 min

37 Which of the following is the most appropriate order? A. LD: Dilantin 1000 mg IV push B. LD: Dilantin 1000 mg IV over 10 minutes C. LD: Dilantin 1000 mg IV in 150 ml of 0.9% NS over 45 minutes (rate ml / 45 minutes about 3.8 ml/min about 22 mg/min) D. LD: Dilantin 1000 mg IV in 150 ml of D5W over 45 minutes (rate ml / 45 minutes about 3.8 ml/min about 22 mg/min)

38 What if you want to give an oral LD?

39 Oral Loading Dose 20 mg/kg phenytoin sodium po in divided doses at 2 3 hour intervals (wt 65 kg) 1300 mg phenytoin sodium Eg. 430 mg (4 x 100 mg, 1 x 30 mg) phenytoin sodium caps po initially (8 am), 430 mg po at 10 am (or 11 am), 430 mg po at 12 noon (or 2 pm)

40 Time to Peak After Single Oral Dose Dose (mg) Peak Time (hrs) Increased peak time with increased dose Low solubility which may lead to prolonged drug input thus prolonged time to peak drug input, thus

41 What to do... To increase the peak concentration and decrease the time required to achieve the peak, large oral doses should be administered in divided doses of mg q 2-3 hours. Applied Pharmacokinetics text

42 LD LD (V D ) (C target ) / (S) (F) (0.65 L/kg) (65 kg) (10 to 20 mg/l) /(0.92)(1.0) 450 mg to 900 mg phenytoin sodium IV or (0.65 L/kg) (65 kg)(10 to 20 mg/l) /(0.92)(0.95) 95) 490 mg to 960 mg phenytoin sodium caps

43 V D What are the determinants of V D? Recall Dr. Cherala s lecture Get your clicker ready

44 What happens to V D as serum albumin decreases i.e. phenytoin protein binding decreases? A) V D increases B) V D decreases C) I don t know

45 V D & Protein Binding Serum Albumin (g/dl) Apparent V D (L/kg) 4.0 normal 0.65 normal Get you clicker ready Both plasma protein binding and tissue binding influence the apparent V D according to the following relationship: up 1.4 V D V plasma + V tissue fut 2.8 f f up fraction unbound plasma f ut fraction unbound tissue

46 Which diseases or conditions alter phenytoin plasma protein binding due to hypoalbuminemia? A) Liver disease B) Nephrotic syndrome C) Burns D) Trauma E) Malnourshment F) Elderly

47 Which diseases or conditions alter phenytoin plasma protein binding due to displacement by endogenous compounds? A) Hyperbilirubinemia B) Jaundice C) Liver disease D) Renal dysfunction

48 Which diseases or conditions alter phenytoin plasma protein binding due to displacement by exogenous compounds? A) Warfarin B) Valproic acid C) Aspirin> 2 g/d D) NSAIDs

49 Which phenytoin PK parameters are affected by hypoalbuminemia or protein binding drug displacement interactions? A) V D B) CL C) T 1/2 D) A and B E) A, B, and C

50 What is the effect of hypoalbuminemia or protein binding drug displacement interactions on phenytoin VD? A) Increase phenytoin V D B) Decrease phenytoin V D C) I don t know

51 V D & Protein Binding V D V plasma + f f up ut V tissue For phenytoin & hypoalbuminemia, f up increases up without a change in tissue binding so V D increases V D V plasma + f f up ut V tissue

52 V D Equation - Hypoalbuminemia V D ( L / kg) 2.8 SerumAlbu min( g / dl)

53 Effect of Valproic Acid on Phenytoin V D Phenytoin & valproic acid are highly protein bound (approx 90%) to the same site on albumin Valproic has a higher affinity for albumin binding site -> competitively ii displaces phenytoin What effect would valproic acid have on phenytoin V D?

54 Effect of Valproic Acid on Phenytoin V D V D up Vplasma + Vtissue f ut f The equation above would predict an increase in phenytoin V D.

55 V D & Renal Failure Decreased phenytoin binding is partly accounted for by decrease in serum albumin Majority of the decreased binding Altered albumin molecule Decreased apparent affinity for albumin due to accumulation of a substance uremic toxin which displaces phenytoin

56 Effect of Chronic Renal Failure on Phenytoin V D Since chronic renal failure reduces [albumin] as well as binding affinity, it is not surprising that the plasma protein binding of phenytoin could be reduced from 90% to 80% i.e f up 0.1 to 0.2. Assuming V plasma and V tissue are unchanged as a consequence of renal failure, what effect would renal failure have on phenytoin V D?

57 Effect of Chronic Renal Failure on Phenytoin V D V D up V plasma + V tissue f ut f The equation above would predict an increase in phenytoin V D.

58 V D Equation Renal Failure V D ( L / kg) SerumAlbu min( g / dl)

59 V D Equation Obesity V D [( IBW ) ( TBW )] 0.65L / kg IBW IBW IdealBodyWeight( kg) TBW TotalBodyWeight( kg)

60 V D Equations V D 0.65 L/kg (range L/kg) If the patient has hypoalbuminemia: V D (L/kg) 2.8/serum albumin (g/dl) If the patient has renal failure: V D (L/kg) 6.5/(1 + serum albumin (g/dl)) If the patients is obese: V D (L/kg) 0.65 L/kg [(IBW)+1.33 (TBW- IBW)]

61 Incremental Loading Dose If the patient is already taking phenytoin but the [phenytoin] is below your target: Incremental LD V D (C targett C observed )/S F

62 Initial Maintenance Dose 5 6 mg/kg TBW divided in 2-3 doses daily and administered q 8 12 hours Calculate a MD for: 65 kg patient? 81.8 kg patient?

63 Initial Maintenance Dose 5 6 mg/kg x 65 kg 325 to 390 mg/d 100 to 130 mg po q 8h 200 mg po q 12 h 5 6 mg/kg x kg 409 to 490 mg/d 400 mg: 200 mg po q 12 h 490 mg: 160 mg po q 8 h

64 What do I do next? Interpret measured phenytoin concentrations

65 Synthesis of information from previous lectures......hepatic clearance...& protein binding

66 Recall The clearance of drug by an eliminating organ depends on the fraction of drug in blood that is available for elimination (fraction of drug unbound in the plasma (f up )), organ blood flow (Q), and intrinsic i i CL (Cl intrinsic ) CL H Q Q + ( CL ) int fup ( CL f ) + int f up

67 CL H Q Q + ( CL f ) int ( up CL f ) int up For low extraction ratio (low E) drugs, changes in f up will affect CL p For drugs that are insufficiently extracted by an elimination organ [(Cl int )(f up )] < Q, and has restrictive CL, then the equation simplifies to: CL CL f H int up Get your clicker ready

68 Protein binding changes (diseases, drug interactions) that increase f u would be expected to: A) Cause an increase in V D and CL, but no change in t 1/2 B) Cause a decrease in V D and CL, but no change in t 1/2 C) Cause no change in V D, CL, and t 1/2

69 Phenytoin (Low E Drug) up V f V V + u H tissue ut plasma D f CL CL V f V V + int ( ) H D D u H CL V t V CL k k t f ; / 2 1/ int D H D CL V t CL V k / CL H

70 Phenytoin (Low E Drug) V D CL ( ) H V plasma ( ) f up + V fut ( ) ( ) CL f ( ) int CL t 1/ 2 ; k t1/ 2 k V u D V CL ( ) ( ) t1/ 2 ( ) H D tissue ( ) CL ( V ) H D

71 Considerations & Impact on C sstotal Since phenytoin has a low extraction ratio and possesses high protein binding, then CL Cl intrinsic x f up Recall, Dose/tau drug infusion rate C ss, total Dose / τ Dose / τ CL CL f int up Get your clicker ready

72 What is the impact of hypoalbuminemia on C ss,total? Dose / τ Dose / τ C ss, total CL CL f A) f up increases, therefore C ss,total increases B) f up increases, therefore C ss,total decreases C) f up increases, but C ss,total does not change. D) No clue. int f up

73 C normal binding These calculations adjust the total phenytoin concentration (C normal binding ) so that it can be compared to the usual phenytoin therapeutic range of mcg/ml The adjusted concentration can then be used to determine if dosage changes are warranted Get your clicker ready

74 For which patients do I need to calculate C normal binding? A) Patients with hypoalbuminemia B) Patients with renal failure C) Patients who are also receiving valproic acid D) A and C only E) All of the above

75 Hypoalbuminemia - C normal binding C C measured normalbind ing ( 0.2 alb )

76 Patient Case Your patient w/epilepsy is being treated w/phenytoin. hypoalbuminemia serum albumin 2.2 g/dl normal renal function total phenytoin concentration 7.5 mcg/ml What do you want to do with this information? Get your clicker ready

77 Please enter your answer Measured phenytoin Cmeasured C concentration 7.5 normalbinding ( 0.2 alb + 0.1) mcg/ml??.?? mcg / ml Serum albumin 2.2 g/dl

78 Renal Failure - C normal binding C C measured normalbind ing ( 0.1 alb )

79 Patient Case Your patient w/epilepsy is being treated w/phenytoin. hypoalbuminemia serum albumin 2.2 g/dl renal lfailure creatinine clearance 10 ml/min total phenytoin concentration 5.5 mcg/ml What do you want to do with this information? Get your clicker ready

80 Please enter your answer Measured phenytoin Cmeasured C concentration 5.5 normalbinding ( 0.1 alb + 0.1) mcg/ml??.?? mcg / ml Serum albumin 2.2 g/dl

81 Valproic Acid -C normal binding C [ ( 0. )( VPA ) ]( DPH ) 01 normalbind ing VPA valproic acid concentration VPA valproic acid concentration DPH phenytoin concentration

82 Patient Case Your patient w/epilepsy is being treated w/phenytoin and valproic acid. normal albumin serum albumin 4.3 g/dl normal renal function creatinine clearance 100 ml/min total phenytoin concentration 7.5 mcg/ml valproic acid concentration 100 mcg/ml What do you want to do with this information? Get your clicker ready

83 Please enter your answer C [ ( 0. )( VPA ) ]( DPH ) normalbindinging 01 Measured phenytoin concentration 7.5 mcg/ml Measured valproic acid concentration 100 mcg/ml

84 What have you learned? What is the impact of alterations in protein binding i.e. an increased f up on C sstotal?

85 Dose / τ Dose / τ Css, total CL CL f int up Protein binding change 20 10?C sstotal Time

86 Dose / τ Dose / τ Css, total CL CL f int up Protein binding change C sstotal Time

87 Considerations & Impact on C ssfree Recall, Dose/tau dose rate C C ss, free ss, free C ss, total f up Dose / τ CL f f Dose / τ CL up int up CL int What is the impact of protein binding alterations ti i.e. an increased f up on C ssfree?

88 Dose / τ C ss, free CL int Protein binding change 20 10?C ssfree Time

89 C ss, free Dose / τ CL int Protein binding change C ssfree Time

90 True or False For a low E drug such as phenytoin, drug interactions or diseases that cause protein binding alterations cause changes in V D, CL, and C ss,total, but no clinically significant change in pharmacologic effect (C ss,free is unchanged).

91 Special Consideration Valproic Acid (VPA) Drug interaction w/phenytoin VPA causes displacement of phenytoin plasma protein binding -> inc f u VPA inhibits Cl int (CYP2C9, CYP2C19)

92 Low extraction; First, effect of dec. Q protein binding i.e. inc f u CL int f u CL V D T 1/2 C ss C ss,free Effect Inc f u Time

93 Special Consideration Valproic Acid (VPA) Fi t i f int f f CL CL u H First inc f u ( ) 2 1/ 2 1/ ; CL V t V CL k k t V f f V V D tissue ut up plasma D + 2 1/ 2 1/ 2 1/ CL V t CL V k H D H D int, / / / Dose f Dose C f CL Dose C up total ss τ τ τ int int, CL f f CL C up up free ss

94 Special Consideration Valproic Acid (VPA) First inc f u ( ) CLH CLint fu ( ) fup ( ) ( ) V V + t 1/ 2 D plasma Vtissue( ) f ( ) ut CL V ; k t 1/ 2 k V CL ( ) ( ) V t1/ 2 ( ) CLH Dose / ( ) Css, total CL ( ) C ss, free int int D Dose / τ CL f up D τ f f up up Dose / τ CL int ( ) H D

95 Low extraction, restrictive clearance; Q First, inc f u. NEXT, dec CL int CL int f u CL V D T 1/2 C ss C ss,free Effect Inc f u Time Dec CL int

96 Special Consideration Valproic Acid (VPA) First inc f u Next, dec CL int ( ) CLH CLint fu ( ) fup ( ) ( ) V V + t 1/ 2 D plasma Vtissue( ) f ( ) ut CL V ; k t 1/ 2 k V CL ( ) ( ) V t1/ 2 ( ) CLH Dose / ( ) Css, total CL ( ) D ( ) D CL V t D 1/ 2 D 1/ 2 C ss, free int int Dose / τ CL f up τ f f up up Dose / τ CL int H t C C H CL int f u fup Vplasma + V f tissue ut CL V ; k t 1/ 2 k V CL V CL ss, total ss, free H int D Dose / τ CL f int up D Dose / τ CL f up f up Dose / τ CL int ( ) H D

97 Special Consideration Valproic Acid (VPA) First inc f u Next, dec CL int ( ) CLH CLint fu ( ) ( ) CLH ( ) CLint fu ( ) f up ( ) ( ) f VD V up plasma + Vtissue( ) ( ) ( ) V V + t 1/ 2 ( ) f ut CL V ; k t 1/ 2 k V CL D ( ) H D t 1/ 2 D plasma Vtissue( ) f ( ) ut CL V ; k t 1/ 2 k V CL ( ) ( ) VD t1/ ( ) ( ) ( ) VD t1/ 2 CLH ( ) CL H Dose / τ ( ) Css, total Dose / τ CLint ( ) ( ) C f ss, total up ( ) CL ( ) C ss, free Dose / τ Dose / τ fup CL f CL ( ) C int up int ss, free int D int Dose / τ f CL f up up f up ( ) H Dose / τ CL ( ) int D

98 Pharmacokinetic Approach......initial iti maintenance doses...adjustments in maintenance doses

99 Nonlinear PK Nonlinear because processes responsible for drug elimination are saturable at [drug] commonly achieved in patients. An increase in drug dose can result in a disproportionate increase in [plasma]

100 Michaelis-Menten PK Model used to describe saturable enzyme systems Allows prediction of plasma drug concentrations resulting from administration of drugs with saturable elimination

101 Michaelis-Menten Menten PK dc dt V k m C + C max -dc/dt rate of [drug] decline over time rate of drug loss K m Michaelis constant [drug] when the rate of elimination is at one-half the maximum (V max ) Expressed in units of concentration (egs mg/l or mcg/ml) V max maximum rate of elimination Expressed in amount per unit time (eg mg/d) Maximum amount of drug eliminated in a given time

102 Relationship of Drug Elimination Rate to Plasma [Drug] V max ½ V max V max /2 k m Plasma [Drug] Get your clicker ready

103 True or False At steady-state, rate of drug in rate of drug out i.e. rate of drug administration rate of drug elimination (drug loss)

104 At steady-state... Rate of Drug Loss Rate of Drug administration (mg/day being removed) (Rate of administration in mg/d) Where, R Rate of administration in mg/d or daily dose RateofDrugAd min istration ( R ) R V k max + m C C V k max + m C C

105 Maintenance Dose Use population V max and k m : R V k max m C + C Vmax C SFR k m + C V max 7mg / kg / d k m 4mg / L If you have dose and concentrations, solve for V max and use population p k m: SFR V k max m SolveForV C + C max SFR ( km + C ) Vmax C :

106 Maintenance Dose For65kgpatient: V 7mg/ kg/ d max 455mg/ d k 4mg / L m ChooseC 12mg / L SFR R V k targ et max m + C C ( 455mg / d)( 12mg / d) mg / d 4mg / L + 12mg / L mg / d mg / d 390mg / d 095)(. 092) Dilantincaps 130mgpoq 8 hours

107 Transform to a straight line... R V k max m + C C R ( k + C ) V C m ( k )( R) + ( C)( R) V C m max max ( C)( R) ( k )( R) + V C DivideBothSidesBy ( C ) R ( k )( R/ C) + V m y mx + b m max max

108 Linear Plot of Michaelis- Menten Equation R ( k )( R/ C) + V m max y mx + b V max Slope -k m R/C steady-state Clearance eg units L/d

109 How can you utilize this information?

110 Steps Used for two or more [phenytoin]-dose pairs Plot R (mg/d) vs R/C (L/d) Draw a line thru the 2 points Y-intercept V max Slope of the line -k m Recall, slope [y 1 y 2 ]/[x 1 x 2 ] Therefore slope [R 1 R 2 ]/[R 1 /C 1 Therefore, slope [R 1 R 2 ]/[R 1 /C ss1 R 2 /C ss2 ]

111 New Dose Michaelis-Menten equation: SFR (V max )(C ss )/k m +C ss Use the values obtained from your plot for V max y-intercept -K m slope

112 Example

113 Case History RJ 70 kg clinic patient Daily dose 300 mg phenytoin sodium C ss 8 mg/l Daily dose was increased to 350 mg phenytoin sodium (bogus-what dosage form did they use in this clinic patient?) 2 months later, daily dose 350 mg phenytoin sodium -> 20 mg/l; pt c/o inability to concentrate

114 Which h ADRs are related to elevated [phenytoin]?

115 Concentration-dependent ADRs > 15 mcg/ml drowsiness or fatigue > 20 mcg/ml nystagmus > 30 mcg/ml ataxia, slurred speech, incoordination > 40 mcg/ml MS changes (decreased mentation, severe confusion or lethargy, coma) > mcg/ml drug-induced seizure activity

116 Which ADRs are associated with chronic therapy but are unrelated to elevated [phenytoin]?

117 ADRs Chronic Therapy Hypertrichosis Gingival hypertrophy Thickening/coarsening of facial features Carbohydrate intolerance/hyperglycemia Folic acid deficiency Vitamin D deficiency Increased vitamin i D metabolism Hypocalcemia; osteomalacia (small subset pts) SLE

118 Process-Ludden Plot R (mg/d) vs R/C (L/d) Both administration rates (R) must be in the same salt form: phenytoin sodium or phenytoin acid R mg phenytoin sodium R 1 /C ss1 300 mg/d / 8 mg/l 37.5 L/d R mg phenytoin sodium R 2 /C ss2 350 mg/d / 20 mg/l 17.5 L/d

119

120 Use your calculator to calculate slope (k m ) and y-intercept (V max )

121 Process Draw a line thru the 2 points: 300 mg/d & 37.5 L/d 350 mg/d & 17.5 L/d Y-intercept V max 393 L/d R. mg/d R/Css, L/d

122 k m Δy [ R R ] slope 1 2 Δx [ R / C R / C ] 1 ss1 2 ss2 [ mg / d ] slope [ L / d] slope + k m k m + 2.5mg 2.5 mg / L / L

123 Determine a dose regimen that would result in a target [phenytoin] of 14 mg/l.

124 Please enter your answer V k max m 393 mg / d 2.5mg / L SFR Vmax C???.? k + C k m Target C ss 14 mg/l

125 What is the most convenient dose to give this patient?

126 330 mg/day phenytoin sodium 3 x 100 mg caps and 1 x 30 mg cap po qd

127 Recall, linearization of Michaelis-Menten Equation R V k max m + C C Rk ( + C) V C m max ( k )( R ) + ( C )( R ) V C m ( C)( R) ( k )( R) + V C R ( k )( R / C ) + V m max DivideBothSidesBy( C) m y mx + b max max

128 Solve for V max R ( km )( R/ C) + Vmax V R + k ( R / C) or max in V ( R/ C) k + R max y mx + b m m If you plot V max vs k m : V max R R y-intercept -C ss x-intercept C ss O k m

129 How are these relationships used clinically?

130 Mullen Method Used for two or more [phenytoin]- dose pairs

131 Orbit Graph Dose Adjustment Sheiner Nomogram g Use R in phenytoin acid Used if you know a single steady-state t t [phenytoin] that reflects a known dosing regimen Orbits represent the fraction of the sample patient population whose k m and V max values are within that orbit

132 Requirements Only for adult patients [Phenytoin] must be an average steadystate value [Phenytoin] must represent the concentrations you would expect when plasma protein binding conditions are normal

133 Average Steady-State State [Phenytoin] - C ss Important for determining V max & k m Required when nomograms are used When to make adjustment: Drug is given qd C tr < 5 mg/l Dose > 400 mg/d

134 Average Steady-State [Phenytoin] - C ss For intermittent short-term IV infusion Assumes C ss is halfway between the C pk & C tr C ss S F Dose + 2V D C trough

135 Average Steady-State [Phenytoin] - C ss For oral: Based upon the observation of a fluctuation at steady-state following oral dosing about half (½ x ½ ¼ ) that observed with IV administration C ss S F Dose 4V D + C trough

136 Adjustments for Protein Binding Hypoalbuminemia i To allow use of total [phenytoin] and the usual ltherapeutic ti range C normal C observed (.)( 02 Salb) C normal is the [phenytoin] that would have been observed if the patient s serum albumin would have been normal.

137 Adjustments for Protein Binding Renal Failure To allow use of total [phenytoin] and the usual ltherapeutic ti range C normalbinding C observed (.)( 01 Salb) C normalbinding is the [phenytoin] that would have been observed if the patient s protein binding/affinity would have been normal.

138 Adjustments for Protein Binding Valproic Acid To allow use of total [phenytoin] and the usual therapeutic range C [ ( 0. )( VPA) ]( DPH ) normalbinding 01 C normalbinding is the [phenytoin] that would have been observed if the patient s protein binding/affinity would have been normal.

139 Pediatric Patients

140 Patient Case

141 CK is a 60 yo 60 kg female patient with alongh/otonic-clonic seizure disorder moderately well-controlled by phenytoin sodium 300 mg po qd. In Seizure Clinic, her total [phenytoin] 5 mg/l with a SCr of 1.3 ml/dl and a serum albumin of 2.0 g/dl. Using the Sheiner nomogram (orbit graph), what are CK s V max & k m?

142 Requirements Only for adult patients [Phenytoin] must be an average steadystate value [Phenytoin] must represent the concentrations you would expect when plasma protein binding conditions are normal R must be in phenytoin acid

143 What is R (mg/kg/d) /d) in phenytoin acid?

144 R (mg/kg/d) R R ( dailydose)( S)( F) Wt ( 300mg / d)( 0. 92)( 0. 95) 60kg R mg / kg / d

145 Patient is on a once-daily regimen with [phenytoin] 5 mg/l SCr 1.3 mg/dl; Salb 2.0 g/dl, wt 60 kg Calculate C ss Need V D Patient has hypoalbuminemia: V D (L/kg) 2.8/serum albumin (g/dl) x Wt (kg) C ss S F Dose 4V D + C trough

146 Average Steady-State [Phenytoin] - Css

147 Patient is on a once-daily regimen with [phenytoin] 5 mg/l SCr 1.3 mg/dl; Salb 2.0 g/dl If the patient has hypoalbuminemia: V D (L/kg) 2.8/serum albumin (g/dl) x Wt (kg) V D (L/kg) 2.8/ 2.0 (g/dl) x Wt (kg) 84 L

148 C ss S F Dose 4V D + C trough 092)(. 095)( 300mg) Css + ( 4)( 84L) C 58. ss mg / L 5mg / L vs. measured phenytoin 5.0 mg/l Next step: [Phenytoin] must represent the concentrations you would expect when plasma protein binding conditions are normal

149 C C normal normal Cobserved ( 0. 2 )( Slb Salb ) mg / L (.)(.) mg / L Cnormal 05. Cnormal 116. mg / L

150 Plot R 4.4 mg/kg/d C ss 11.6 mg/l V max? K m?

151

152

153 mg/kg/d

154 K m 5.5 mg/l V max 6.5 mg/kg/d x 60 kg 390 mg/d What if you want to increase C ss to 15 mg/l? ( V )( C ) Calculate: SFR SFR R max ss km + Css ( 390 mg / d )( 15 mg / L ) 55. mg / L + 15mg / L mg / d mg / d mg / d ( )( )

155

156 Or plot: Red line crosses y-axis at 5 mg/kg/d phenytoin acid: R ( 5mg / kg / d )( 60 kg ) 343mg / d 330mg / d 092)(. 095)

157 Despite your recommendations, CK s phenytoin dose is increased to phenytoin sodium capsules 200 mg po bid. Six months later, CK s total [phenytoin] is found to be 18 mg/l and she is demonstrating nystagmus & ataxia. SCr 1.0; Salb 2.0 Is the [phenytoin] at steady-state? state? Use the Mullen method to determine V max &k m. What are your recommendations at this time?

158 Time to Achieve 90% of SS km VD t90% 2 (. 23 Vmax 09. Rin ) ( V R ) t t max in 55. mg / L 84L ( 390mg / d 350mg / d) 90% 2 462mg ( 897mg / d 315mg / d) ( 40mg / d) 90% 2 2 t90% d mg 582mg d (. / )( / ) t 168days 56. months 90% ( 2. 3 ( 390mg / d) 0. 9 ( 350mg / d) R 200 mg po bid 400 mg/d (400 mg/d)(0.92)(0.95) 350 mg phenytoin acid See Applied PK text for derivation

159 Mullen (Cornish-Bowden) Method Used for two or more [phenytoin]- dose pairs

160 Requirements Only for adult patients [Phenytoin] must be an average steadystate value [Phenytoin] must represent the concentrations you would expect when plasma protein binding conditions are normal R must be in phenytoin acid

161 Recall Phenytoin sodium caps Phenytoin sodium caps 300 mg po qd 200 mg gpo BID 400 mg/d R mg/kg/d R 2?mg/kg/d phenytoin acid phenytoin acid C trough 5 mg/l C trough 18 mg/l C normal 11.6 mg/l C normal?

162 What is R 2 (mg/kg/d)?

163 R 2 (mg/kg/d) R 2 R 2 2 ( dailydose)( S)( F) Wt ( 400mg / d)( 0. 92)( 0. 95) 60kg R 58. mg / kg / d 2

164 Calculate C ss Need V D Patient has hypoalbuminemia: V D (L/kg) 2.8/serum albumin (g/dl) x Wt (kg) V D (L/kg) 2.8/ 2.0 (g/dl) x 60 (kg) 84 L C ss S F Dose 4V V D + C trough

165 C ss S F Dose 4V D + C trough (. 0 92)(. 0 95)( 200mg) Css + ( 4)( 84L) C 185. ss mg / L 18mg / L vs. measured phenytoin 18.0 mg/l Next step: [Phenytoin]must represent the concentrations you would expect when plasma protein binding conditions are normal

166 C normal C observed (.)( 02 Salb) C normal 185. mg / L ( 0. 2 )( 2. 0 ) C normal C 37mg / L! normal 185. mg / L 05.

167 Recall Phenytoin sodium caps Phenytoin sodium caps 300 mg po qd 200 mg gpo BID 400 mg/d R mg/kg/d in R mg/kg/d in phenytoin acid phenytoin acid C normal 11.6 mg/l C normal 37 mg/l

168 R, V max, mg/kg/d g C ss mg/l K m mg/l

169 Interpret Graph See point where lines intersect Locate on y-axis gives you V max Locate on x-axis gives you k m

170 Determine a new dosing regimen to achieve a target of 15 mg/l. (normalized for protein binding)

171 R, V max, 6 mg/kg/d g C ss mg/l K m mg/l

172 New Dose V max 6.8 mg/kg/d, k m 6 mg/l 2methods: Use plot (see green line from point of intersection to 15 mg/l): crosses x-axis at 5 mg/kg/d x 60 kg 300 mg/ phenytoin acid 343 mg/d or 330 mg/d phenytoin sodium

173 New Dose Rearrange the Michaelis-MentenMenten equation: SFR (V max )(C ss )/k m + C ss Use the values obtained from your plot for V max 6.8 mg/kg/d 408 mg/d K m 6 mg/l SFR (V max )(C ss )/k m + C ss SFR (408 mg/d)(15mg/l)/6 )/ mg/l+15 mg/l SFR 291 mg/d phenytoin acid R 291 mg/d/(0.92)(0.95) 333 mg/phenytoin sodium

174 How long should ldih hold ldthe dose?

175 t t t C 0 ( km ) ln + ( Co Ct) Ct V / V max ( 6. 0mg / L ) ln D 37mg / L + ( 37mg / L 15mg / L ) 15mg / L 408mg / d / 84L 54. mg / L + 22mg / L 56. days 6days 49. mg / d / L What is an appropriate order?

176 Check free [phenytoin]. Hold phenytoin doses. Check [phenytoin] q 2-3 days to assess trends. Restart phenytoin sodium 330 mg po qd when [phenytoin] < 15 mg/l (normalized) or < 7.5 mg/l (observed).

177 How about same scenario using a different method? Ludden Method

178 Recall Phenytoin sodium caps 300 mg po qd R mg/d phenytoin acid C normal 11.6 mg/l R 1 /C 22.6 L/d Phenytoin sodium caps 200 mg po BID 400 mg/d R mg/d phenytoin acid C normal 37 mg/l R 2 /C 9.5 L/d

179 Process Plot R (mg/d) vs R/C (L/d) Both administration rates (R) must be in the same salt form: phenytoin sodium or phenytoin acid R mg phenytoin acid R 1 /C ss L/d R 2 2/ /C ss2 9.5 L/d R mg phenytoin acid Use your calculator to calculate slope (k m )and y-intercept (V max )

180 Process Draw a line thru the 2 points: 262mg/d & 22.6 L/d 350 mg/d & 9.5 L/d Y-intercept V max L/d R. mg/d R/Css, L/d

181 k m slope [ R R ]/[ R / C ] [ R C ] ss1 2 ss2 slope [ mg / d]/[ L / d] slope km 6. 7mg / L km 6. 7 mg / L

182 New dose Vmax mg/ d km 67. mg/ L ( Vmax )( Css ) SFR km + Css ( mg / d )( 15mg / L ) SFR 67. mg / L + 15mg / L 286mg / dphenytoinacid 327mg / dphenytoinsodium 330mg / dphenytoinsodium

183 Questions?