phenytoin pk lecture

Phenytoin PKPhenytoin PK

Myrna Y. Munar, Pharm.D., BCPSAssociate ProfessorAssociate Professor

Clickers

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ObjectivesObjectives 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 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 tophenytoin 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(effectiveness, toxicity, protein binding, renal or hepatic function)

Calculate PK parameters and formulate changes if necessary based upon patient info, desired therapeutic goals, andbased upon patient info, desired therapeutic goals, and phenytoin concentration data

Oral Bioavailability (F)

F = 0.95 1.0

Dilantin ProductsPhenytoin Acid

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

S 1 0 S = 1.0

Dilantin ProductsPhenytoin Acid

Ch bl Chewable Convenient pediatric

d fdosage form 50 mg phenytoin

acidacid S = 1.0

Phenytoin sodium = 92% phenytoinS = 0.92S 0.92

Dilantin ProductsPhenytoin Sodium

Extended phenytoinsodium capsules30 30 mg

100 mgFDA h ti d FDA has cautioned use of any product other than Dilantinother than DilantinKapseals for once-a-day useS 0 92 S = 0.92

Parenteral ProductsPhenytoin SodiumPhenytoin Sodium

Dilantin IV 50 mg/mlg Phenytoin sodium Rate of administration not to exceed Rate of administration not to exceed

50 mg/min; 25 mg/min in elderly patients or patients with cardiacpatients or patients with cardiac diseaseS 0 92 S = 0.92

Parenteral ProductsPhenytoin SodiumPhenytoin Sodium Fosphenytoin (Cerebyx)

Al ib i h t i di Always prescribe in phenytoin sodium equivalents!

75 mg/ml fosphenytoin = 50 mg/ml of 75 mg/ml fosphenytoin = 50 mg/ml of phenytoin sodium equivalents

2 ml per vial: 150 mg = 100 mg of p g gphenytoin sodium equivalents

10 ml per vial: 750 mg = 500 mg of h t i di i l tphenytoin sodium equivalents

Rate of administration not to exceed 150 mg phenytoin sodium150 mg phenytoin sodium equivalents/min

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 vivoresolved with adequate in vitro or in vivo evidence supporting bioequivalence.100 mg 200 mg 300 mg capsules 100 mg, 200 mg, 300 mg capsules

S = 0.92

Bi il bilit bl ithBioavailability problems with generic product....generic product....

Effect of Food:Effect of Food:Dilantin Kapseals vs Mylan Product

N = 24 healthy volunteers Non blinded single-dose randomized Non blinded, single dose, randomized,

two-period, two-way crossover study 8-hour overnight fast 8-hour overnight fast Dilantin or Mylan in random order at 2-

week intervalsweek intervals Both products administered with a high-fat

breakfastbreakfast Wilder BJ et al. Neurology 2001;57(4):582-9

Effect of Food:Effect of Food:Substituting Mylan Product for Dilantin Kapseals

Open circle: Mylan AUC 29.4 mgxhr/Lg / Solid circle: Dilantin AUC 33.9 mgxhr/L AUC 33.9 mgxhr/L What is the relative

F of Mylan:Dilantin?o y a a t

Relative Bioavailability

( )DoseAUCF /( )( )AA DoseAUC

DoseAUCFF

//= ( )BB DoseAUCF /

Relative Bioavailability( )( )( )

( )//=DoseAUCDoseAUC

FF

B

A

B

A

( )( )100//9.33

100//4.29=

mgLhrmgmgLhrmg

13% reduction in the amount of phenytoin

87.0=

sodium absorbed when Mylan product taken w/food is substituted for Dilantin

95%CI 81 4 92 4% doe not in l de 100% the efo e 95%CI 81.4-92.4%; does not include 100%, therefore statistically significant

Conversely....Conversely....

Effect of Food:Effect of Food:Substituting Dilantin Kapseals for Mylan Product

SAME DATA: Open circle: Mylanp y AUC 29.4 mgxhr/L Solid circle: Dilantin Solid circle: Dilantin AUC 33.9 mgxhr/L What is the relative What is the relative

F of Dilantin:Mylan?

Relative Bioavailability

( )DoseAUCF /( )( )AA DoseAUC

DoseAUCFF

//= ( )BB DoseAUCF /

Relative Bioavailability( )( )

( )100//933//=

LhDoseAUCDoseAUC

FF

B

A

B

A

( )( )

15.1100//4.29100//9.33

==

mgLhrmgmgLhrmg

15% increase in the amount of phenytoin sodium absorbed when Dilantin taken w/food is

15.1

sodium absorbed when Dilantin taken w/food is substituted for Mylan product 95%CI 81.4-92.4%; does not include 100%, 95%CI 81.4 92.4%; does not include 100%,

therefore statistically significant

Translate information toinformation to predicted steady-state plasma p[phenytoin]

A: Dilantin to Mylan13% d i F 13% decrease in F predicted to result in median 37% d ldecrease in plasma [phenytoin]

B: Mylan to Dilantin B: Mylan to Dilantin 15% increase in F

predicted to result in 102% increase in102% increase in median plasma [phenytoin]

What is your advice?What is your advice?

Mephenytoin (Mesantoin)Mephenytoin (Mesantoin)This is an entirely different drug!

Therapeutic range is different Therapeutic range is different 25-40 mcg/ml

PK PK Rapidly absorbed with Cpeak within 1 hour Parent drug t1/2 = 7 17 hrs Active major metabolite t1/2 = 96 114 /

hours Less extensive protein binding = 60% free,

b dunbound

Mephenytoin (Mesantoin)

ADRs (vs phenytoin) Lower incidence of gingival hyperplasia Lower incidence of gingival hyperplasia,

ataxia, hirsutism, gastric upset Greater risk of serious side effects: bloodGreater risk of serious side effects: blood

dyscrasias, serious dermatologic reactions, SLE, & hepatotoxicity

Phenytoin PKPhenytoin PK

What do I do first?What do I do first?

Determine loading doseDetermine maintenance doseDetermine maintenance dose

Loading Dose

Patients not already receiving phenytoin Patients already receiving phenytoin Patients already receiving phenytoin Based on patients total body weight

b ( d l ) d d In obese (adult) patients, use adjusted body weight (ABW) = IBW + [1.33 ( )](TBW IBW)]

Patients not already receiving phenytoin

IV loading 2 methods: 15 20 mg/kg x TBW or ABW (kg) 15 20 mg/kg x TBW or ABW (kg) LD = (VD) (C target) / (S) (F)

Calculate an IV LD

For a 65 kg nonobese patient

IV LD

For a 65 kg nonobese patient 15 mg/kg x 65 kg = 975 mg phenytoin 15 mg/kg x 65 kg = 975 mg phenytoin

sodium IVLets choose 1000 mg phenytoin sodium Lets choose 1000 mg phenytoin sodium IV

Parenteral ProductsPhenytoin Sodium

Dilantin IV 50 mg/ml Phenytoin sodium Phenytoin sodium 2 ml sterile syringe

2 ml & 5 ml sterile vials 2 ml & 5 ml sterile vials

IV Admixture

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

mg/ml

1000 mg phenytoin sodium/50 mg/mlmg/ml

= 20 ml4 5 l i l 20 l4 x 5 ml vials = 20 ml

Phenytoin IV

Dilution prior to IV administration Use 50 150 ml of 0.9% saline or Lactated

Ringers Do not use D5W, insoluble & precipitates!

f h l f l ( Infuse thru an in-line filter (eg 0.22 micron filter)

Infusion rate not to exceed 50 mg/min; Infusion rate not to exceed 50 mg/min; 25 mg/min in elderly patients or

patients with cardiac diseasepatients with cardiac disease

Wh t i th i i i f iWhat is the minimum infusion time for this patient?time for this patient?

1000 mg/50 mg/min1000 mg/50 mg/min=20 min

Which of the following is the most appropriate order?

A. LD: Dilantin 1000 mg IV push B. LD: Dilantin 1000 mg IV over 10 minutesg C. LD: Dilantin 1000 mg IV in 150 ml of 0.9%

NS over 45 minutes (rate = 150 + 20 = 170ml / ( /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 = 150 + 20 = 170ml / 45

i t b t 3 8 l/ i b t 22 / i )minutes about 3.8 ml/min about 22 mg/min)

Wh t if t t iWhat if you want to give an oral LD?oral LD?

Oral Loading Dose

20 mg/kg phenytoin sodium po in divided doses at 2 3 hour intervals (wtdivided doses at 2 3 hour intervals (wt = 65 kg)

1300 mg phenytoin sodium 1300 mg phenytoin sodium Eg. 430 mg (4 x 100 mg, 1 x 30 mg)

phenytoin sodium caps po initially (8phenytoin sodium caps po initially (8 am) , 430 mg po at 10 am (or 11 am), 430 mg po at 12 noon (or 2 pm)430 mg po at 12 noon (or 2 pm)

Time to Peak AfterSingle Oral Dose

Increased peak time with increased doseDose (mg) Peak Time Low solubility which

may lead to prolonged drug input thus

Dose (mg) Peak Time (hrs)

400 8 4 drug input, thus prolonged time to peak

4008001600

8.413.231 51600 31.5

What to do...

To increase the peak concentration and decrease the time required toand decrease the time required to achieve the peak, large oral doses should be administered in divided dosesshould be administered in divided doses of 200 400 mg q 2-3 hours.

Applied Pharmacokinetics text

LD LD = (VD) (C target) / (S) (F)

(0 65 L/k ) (65 k ) (10 t 20 /L) (0.65 L/kg) (65 kg) (10 to 20 mg/L) /(0.92)(1.0) = 450 mg to 900 mg phenytoin sodium IV orphenytoin sodium IV or

(0.65 L/kg) (65 kg)(10 to 20 mg/L) /(0 92)(0 95) = 490 mg to 960 mg/(0.92)(0.95) = 490 mg to 960 mg phenytoin sodium caps

VD What are the determinants of VD?

Recall Dr Cheralas lecture Recall Dr. Cherala s lecture

G t li k d Get your clicker ready

What happens to VD as serum albumin decreases i e phenytoin protein bindingdecreases i.e. phenytoin protein binding decreases?

A) VD increasesB) V decreasesB) VD decreasesC) I dont know

VD & Protein Binding Both plasma protein

binding and tissue binding influence the

Serum Albumin (g/dl)

Apparent VD (L/kg) binding influence the

apparent VD according to the following relationship:4.0 normal 0.65 normal relationship:

3.02.0

0.91.4 tissue

upplasmaD Vf

fVV

+=2.0

1.01.42.8

f = fraction unbound plasma

tissueut

plasmaD f fup = fraction unbound plasmafut = fraction unbound tissue

Get you clicker ready

Which diseases or conditions alter phenytoin plasma protein binding due toplasma protein binding due to hypoalbuminemia?

A) Liver diseaseB) Nephrotic syndromeB) Nephrotic syndromeC) BurnsD) TraumaE) MalnourshmentF) Elderly

Which diseases or conditions alter phenytoin plasma protein binding due to displacement byplasma protein binding due to displacement by endogenous compounds?

A) HyperbilirubinemiaB) JaundiceB) JaundiceC) Liver diseaseD) Renal dysfunction

Which diseases or conditions alter phenytoin plasma protein binding due to displacement byplasma protein binding due to displacement by exogenous compounds?

A) WarfarinB) Valproic acidB) Valproic acidC) Aspirin> 2 g/dD) NSAIDs

Which phenytoin PK parameters are affected by hypoalbuminemia or protein binding drughypoalbuminemia or protein binding drug displacement interactions?

A) VDB) CLB) CLC) T1/2D) A and BE) A, B, and C

What is the effect of hypoalbuminemia or protein binding drug displacement interactionsprotein binding drug displacement interactions on phenytoin VD?

A) Increase phenytoin VDB) Decrease phenytoin VB) Decrease phenytoin VDC) I dont know

VD & Protein Binding

tissueup

plasmaD Vff

VV

+=

utp f

For phenytoin & hypoalbuminemia, fup increases upwithout a change in tissue binding so VDincreases

tissuet

upplasmaD Vf

fVV

+=

utf

VD Equation - Hypoalbuminemia

82)/min(

8.2)/(dlgSerumAlbu

kgLVD =

Effect of Valproic Acid on Phenytoin VD

Phenytoin & valproic acid are highly protein bound (approx 90%) to the same site on albumin

Valproic has a higher affinity for albumin bi di i i i l di lbinding site -> competitively displaces phenytoinWh t ff t ld l i id h What effect would valproic acid have on phenytoin VD?

Effect of Valproic Acid on Phenytoin VD

iup

lD Vf

VV

+= tissue

utplasmaD Vf

VV

+

The equation above would predict an increase in phenytoin VD.

VD & Renal Failure

Decreased phenytoin binding is partly accounted for by decrease in serumaccounted for by decrease in serum albumin

Majority of the decreased binding Majority of the decreased binding Altered albumin molecule

Decreased apparent affinity for albumin Decreased apparent affinity for albumin due to accumulation of a substance uremic toxin which displaces phenytoinuremic toxin which displaces phenytoin

Effect of Chronic Renal Failure onEffect of Chronic Renal Failure on Phenytoin VD

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 fup 0.1 to 0 2to 0.2.

Assuming Vplasma and Vtissue are unchanged as a consequence of renal failure what effecta consequence of renal failure, what effect would renal failure have on phenytoin VD?

Effect of Chronic Renal FailureEffect of Chronic Renal Failureon Phenytoin VD

tissueup

plasmaD Vf

VV

+= tissue

utplasmaD Vf

VV

The equation above would predict an increase in phenytoin VDp y D.

VD Equation Renal Failure

)/min(15.6)/(

dlgSerumAlbukgLVD +=

VD Equation Obesity

( ) ( )[ ]33.1/65.0 IBWTBWIBWkgLVD +=)()(

kgeightTotalBodyWTBWkgeightIdealBodyWIBW

==

VD Equations

VD = 0.65 L/kg (range 0.6 0.7 L/kg) If the patient has hypoalbuminemia: If the patient has hypoalbuminemia:

VD (L/kg) = 2.8/serum albumin (g/dl) If the patient has renal failure: If the patient has renal failure:

VD (L/kg) = 6.5/(1 + serum albumin (g/dl)) If the patients is obese: If the patients is obese:

VD (L/kg) = 0.65 L/kg [(IBW)+1.33 (TBW-IBW)])]

Incremental Loading Dose

If the patient is already taking phenytoin but the [phenytoin] is belowphenytoin but the [phenytoin] is below your target: Incremental LD = VD (C t t C b d)/S F Incremental LD VD (C target Cobserved)/S F

Initial Maintenance Dose

5 6 mg/kg TBW divided in 2-3 doses daily and administered q 8 12 hoursdaily and administered q 8 12 hours

Calculate a MD for:65 kg patient = ? 65 kg patient = ?

81.8 kg patient = ?

Initial Maintenance Dose

5 6 mg/kg x 65 kg = 325 to 390 mg/d 100 to 130 mg po q 8h 100 to 130 mg po q 8h 200 mg po q 12 h

5 6 mg/kg x 81 8 kg = 409 to 490 5 6 mg/kg x 81.8 kg = 409 to 490 mg/d

400 mg: 200 mg po q 12 h 400 mg: 200 mg po q 12 h 490 mg: 160 mg po q 8 h

What do I do next?What do I do next?

Interpret measured phenytoin concentrations

S th i f i f ti fSynthesis of information from previous lectures...previous lectures...

...hepatic clearance

...& protein binding...& protein binding

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 )) bl d fl (Q) d i t i i(fup)), organ blood flow (Q), and intrinsic CL (Clintrinsic)

( )( )upH fCLQ fCLQCL + = int( )upfCLQ + int

( )( )upfCLQCL = int( )upH fCLQCL += int For low extraction ratio (low E) drugs,

changes in fup will affect CLp For drugs that are insufficiently

extracted by an elimination organ [(Clint)(fup)] < Q, and has restrictive CL, then the equation simplifies to:

upH fCLCL = intGet your clicker ready

Protein binding changes (diseases, drug interactions) that increase f would beinteractions) that increase fu would be expected to:

A) Cause an increase in VD and CL, but no change in t1/2no change in t1/2

B) Cause a decrease in VD and CL, but no change in tno change in t1/2

C) Cause no change in VD, CL, and t1/2

Phenytoin (Low E Drug)

up Vf

VV

+=

uH

tissueut

plasmaD

fCLCL

Vf

VV

=

+=

int ( )H

D

D

uH

CLVt

VCLk

kt

f

=== 693.0;693.0 2/12/1int

D

HD

CLVt

CLVk= 693.02/1HCL

Phenytoin (Low E Drug)

( ) ( ) ( )up VfVV +( ) ( )( ) ( )( ) ( )uH

tissueut

pplasmaD

fCLCL

Vf

VV

=

+=

int ( )( ) H

D

D

VCL

VtVCLk

kt

===

6930

693.0;693.0 2/12/1

( ) ( )( ) H DCLVt

= 693.02/1

Considerations & Impact on Csstotal Since phenytoin has a low extraction

ratio and possesses high protein binding, then CL = Clintrinsic x fup

Recall, Dose/tau = drug infusion rate

DoseDose // up

totalss fCLDose

CLDoseC == int,

//

Get your clicker ready

What is the impact of hypoalbuminemia on Css,total?

totalss fCLDose

CLDoseC ==, //

A) fup increases, therefore Css,total increases

upfCLCL intp ,

B) fup increases, therefore Css,total decreasesC) fup increases, but Css total does not change.up ss,total gD) No clue.

Cnormal binding These calculations adjust the total

phenytoin concentration (Cnormal binding)phenytoin concentration (Cnormal binding) so that it can be compared to the usual phenytoin therapeutic range of 10 20phenytoin therapeutic range of 10 20 mcg/ml

The adjusted concentration can then be The adjusted concentration can then be used to determine if dosage changes are warrantedare warranted


For which patients do I need to calculate Cnormal binding?

A) Patients with hypoalbuminemiaB) Patients with renal failureB) Patients with renal failureC) Patients who are also receiving

valproic acidvalproic acidD) A and C onlyE) All of the above

Hypoalbuminemia - Cnormal binding

C( )1.02.0 += alb

CC measuredingnormalbind ( )

Patient Case

Your patient w/epilepsy is being treated w/phenytoin. hypoalbuminemia

serum albumin = 2.2 g/dl

l l f ti normal renal function total phenytoin concentration = 7.5 mcg/ml

What do you want to do with this What do you want to do with this information?


Please enter your answer

Measured phenytoin concentration = 7.5CC measured= concentration 7.5 mcg/ml

Serum albumin =

( )mlmcg

albC ingnormalbind

/??.??1.02.0

=+=

2.2 g/dlg

Renal Failure - Cnormal binding

C( )1010 += alb

CC measuredingnormalbind ( )1.01.0 +alb

Patient Case

Your patient w/epilepsy is being treated w/phenytoin. hypoalbuminemia

serum albumin = 2.2 g/dl

l f il renal failure creatinine clearance 10 ml/min

total phenytoin concentration = 5.5 mcg/mltotal phenytoin concentration 5.5 mcg/ml

What do you want to do with this information?


Please enter your answer

Measured phenytoin concentration = 5.5CC measured= concentration 5.5 mcg/ml

Serum albumin =

( )mlmcg

albC ingnormalbind

/??.??1.01.0

=+=

2.2 g/dlg

Valproic Acid - Cnormal binding

( )( )[ ]( )DPHVPAC ilbi d 01.095.0 += ( )( )[ ]( )DPHVPAC ingnormalbind 01.095.0 +VPA = valproic acid concentrationVPA = valproic acid concentrationDPH = phenytoin concentration

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 valproic acid concentration = 100 mcg/ml What do you want to do with this

information?information?Get your clicker ready

Please enter your answer Measured phenytoin

concentration = 7.5 ( )( )[ ]( )DPHVPAC ingnormalbind 01.095.0 +=mcg/ml

Measured valproic

( )( )[ ]( )ingnormalbind

acid concentration = 100 mcg/ml

What have you learned?

What is the impact of alterations in protein binding i.e. an increased fup onprotein binding i.e. an increased fup on Csstotal?

lDoseDoseC == //

uptotalss fCLCL

C int,

Protein binding change

20


10?Csstotal

Time

DoseDoseC == // up

totalss fCLCLC == int,


20


10Csstotal

Time

Considerations & Impact on Cssfree Recall, Dose/tau = dose rate

fCC =

,

,,

//CL

DoseffCL

DoseC

fCC

upfreess

uptotalssfreess

===

What is the impact of protein bi di lt ti i i d

intint CLfCL up

binding alterations i.e. an increased fup on Cssfree?

/DoseC f=

int, CL

C freess


20


10

?Cssfree

Time

/C

DoseC freess=

int, CLfreess


20


10

Cssfree

Time

True or False

For a low E drug such as phenytoin, drug interactions or diseases that causeinteractions or diseases that cause protein binding alterations cause changes in VD, CL, and Css total, but nochanges in VD, CL, and Css,total, but no clinically significant change in pharmacologic effect (Css free ispharmacologic effect (Css,free is unchanged).

Special ConsiderationpValproic Acid (VPA)

Drug interaction w/phenytoin VPA causes displacement of phenytoin VPA causes displacement of phenytoin

plasma protein binding -> inc fu VPA inhibits Clint (CYP2C9, CYP2C19)VPA inhibits Clint (CYP2C9, CYP2C19)

Low extraction; First effect of decLow extraction; First, effect of dec. protein binding i.e. inc fu

QQCLintffuCLVDVDT1/2CssssCss,freeEffect

TimeInc fu

Special ConsiderationValproic Acid (VPA)

Fi t i f

int

ffCLCL uH

=

First inc fu

( )2/12/1

693.0;693.0CL

VtVCLk

kt

Vff

VV

D

tissueut

upplasmaD

===

+=

2/1

2/12/1

693.0CL

Vt

CLVk

H

D

HD

=

int,

//

/

DosefDoseC

fCLDoseC

uptotalss

=

intint, CL

ffCL

C upup

freess ==


Fi t i f

( ) ( )( ) ( ) ( )

int

f

fCLCL uH

=

First inc fu

( ) ( )( ) ( )( )

2/12/1693.0;693.0 VtCLkt

Vff

VV

D

tissueut

upplasmaD

===

+=

( ) ( )( )2/12/12/1

693.0

;

CLVt

CLVk

H

D

HD

= ( )

( ) ( )int,//

/

DoseDosefCL

DoseCup

totalss

=

intint,

//CL

DoseffCL

DoseC upup

freess ==

Low extraction restrictive clearance;Low extraction, restrictive clearance; First, inc fu. NEXT, dec CLint

QQCLintffuCLVDVDT1/2CssssCss,freeEffect

TimeInc fu Dec CLint


Fi t i f N t d CL

( ) ( )( ) ( ) ( )

int

f

fCLCL uH

= int

ffCLCL uH

=

First inc fu Next, dec CLint

( ) ( )( ) ( )( )

2/12/1693.0;693.0 VtCLkt

Vff

VV

D

tissueut

upplasmaD

===

+=

( )2/12/1

693.0;693.0 VtCLkt

Vff

VV

D

tissueut

upplasmaD

===

+=

( ) ( )( )2/12/12/1

693.0

;

CLVt

CLVk

H

D

HD

= 2/1

2/12/1

693.0

;

CLVt

CLVk

H

D

HD

=( )( ) ( )int,

//

/

DoseDosefCL

DoseCup

totalss

= int,

//

/

DoseDosefCL

DoseCup

totalss

=

intint,

//CL

DoseffCL

DoseC upup

freess == intint,

//CL

DoseffCL

DoseC upup

freess ==


Fi t i f N t d CL

( ) ( )( ) ( ) ( )

int

f

fCLCL uH

= ( ) ( ) ( )

( ) ( )int

f

fCLCL uH

=

First inc fu Next, dec CLint

( ) ( )( ) ( )( )

2/12/1693.0;693.0 VtCLkt

Vff

VV

D

tissueut

upplasmaD

===

+= ( ) ( )( ) ( )

( )2/12/1

693.0;693.0 VtCLkt

Vff

VV

D

tissueut

upplasmaD

===

+=

( ) ( )( )2/12/12/1

693.0

;

CLVt

CLVk

H

D

HD

= ( ) ( )( )2/1

2/12/1

693.0

;

CLVt

CLt

Vk

kt

H

D

HD

=

( )( ) ( )int,

//

/

DoseDosefCL

DoseCup

totalss

=

( )( ) ( ) ( )( )

int,

//

/

DoseDosefCL

DoseCup

totalss

H

=

intint,

//CL

DoseffCL

DoseC upup

freess == ( ) ( ) intint,

//CL

DoseffCL

DoseC upup

freess ==

Pharmacokinetic Approach...

i iti l i t d

Pharmacokinetic Approach...

...initial maintenance doses...adjustments in maintenance doses

Nonlinear PK

Nonlinear because processes responsible for drug elimination areresponsible for drug elimination are saturable at [drug] commonly achieved in patients.in patients.

An increase in drug dose can result in a disproportionate increase in [plasma]disproportionate increase in [plasma]

Michaelis-Menten PK

Model used to describe saturable enzyme systemsenzyme systems

Allows prediction of plasma drug concentrations resulting fromconcentrations resulting from administration of drugs with saturable eliminationelimination

Michaelis-Menten PKMichaelis Menten PK = +dcdt

V Ck Cm

max

-dc/dt = rate of [drug] decline over time = rate of drug loss

Km = Michaelis constant [drug] when the rate of elimination is at

one-half the maximum (V )one-half the maximum (Vmax) Expressed in units of concentration (egs

mg/L or mcg/ml) Vmax = maximum rate of elimination

Expressed in amount per unit time (eg mg/d)mg/d)

Maximum amount of drug eliminated in a given time

Relationship of Drug Elimination p gRate to Plasma [Drug]

Vmax

Vmax=Vmax/2

Plasma [Drug]km Plasma [Drug]kmGet your clicker ready

True or False

At steady-state, rate of drug in = rate of drug out i.e. rate of drug administrationdrug out i.e. rate of drug administration = rate of drug elimination (drug loss)

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 doseWhere, R = Rate of administration in mg/d or daily dose

CVAdf )(i

CVCkCVRistrationAdRateofDrug

m += max)(min

CkCVR

m += max

Maintenance Dose

Use population Vmax and km: If you have dose and concentrations,solve for Vmax and use population km:

CkCVR

m

max

+=

CkCVSFR

m

max

+=

max p p m

CkCVSFR max+=

CkSFRSolveForV

m

)(:max+

dkgmgVCkm

//7max =+

CCkSFRV m )(max

+=

Lmgkm /4=

Maintenance DoseFor kgpatientV mg kg d mg d

657 455

:/ / /max = =

k mg LChooseC mg Lm

t et

412

//arg

==

SFRV Ck C

mg d mg dmg L mg L

mg dm

455 124 12

3413( / )( / )

/ /. /max= + = + =

Rmg d

mg d mg d

Dil ti h

34130 95 0 92

3905 390

130 8

. /( . )( . )

. / /= = Dilantincaps mgpoq hours130 8

Transform to a straight lineTransform to a straight line...

V C = +RV Ck C

R k C V Cm

max

( )+ =+ =

R k C V Ck R C R V C

m

m

max

max

( )( )( ) ( )( )

= +C R k R V CDivideBothSidesBy C

m max( )( ) ( )( )( )

= +DivideBothSidesBy CR k R C V

bm max

( )( )( / )

= +y mx b

Linear Plot of Michaelis-Menten Equation

R k R C Vy mx b

m= + +

( )( / ) maxy mx b = +

VSlope = -km

Vmax

R/Csteady-state=Clearance eg units L/d

H tili thiHow can you utilize this information?information?

Steps

Used for two or more [phenytoin]-dose pairsp

Plot R (mg/d) vs R/C (L/d) Draw a line thru the 2 pointsDraw a line thru the 2 points Y-intercept = Vmax Slope of the line = -k Slope of the line = km

Recall, slope = [y1 y2]/[x1 x2] Therefore slope = [R1 R2]/[R1/C 1 Therefore, slope = [R1 R2]/[R1/Css1

R2/Css2]

New Dose

Michaelis-Menten equation: SFR = (V )(C )/k + C SFR (Vmax)(Css)/km + Css

Use the values obtained from your plot forfor Vmax = y-intercept

K slope -Km = slope

ExampleExample

Case History

RJ 70 kg clinic patient Daily dose 300 mg phenytoin sodiumy g p y

Css 8 mg/L Daily dose was increased to 350 mg y g

phenytoin sodium (bogus-What dosage form did they use in this clinic patient?)

2 th l t d il d 350 2 months later, daily dose 350 mg phenytoin sodium -> 20 mg/L; pt c/o inability to concentrateinability to concentrate

Whi h ADR l t d tWhich ADRs are related to elevated [phenytoin]?elevated [phenytoin]?

Concentration-dependent ADRs > 15 mcg/ml

drowsiness or fatigue > 20 mcg/ml > 20 mcg/ml

nystagmus > 30 mcg/ml

ataxia, slurred speech, incoordination > 40 mcg/ml

MS changes (decreased mentation, severe confusion or lethargy, g ( , gy,coma)

> 50-60 mcg/ml drug-induced seizure activityg y

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

ADRs Chronic Therapy Hypertrichosis Gingival hypertrophy Thickening/coarsening of facial features Carbohydrate intolerance/hyperglycemia Folic acid deficiency Vitamin D deficiency

I d i i D b li Increased vitamin D metabolism Hypocalcemia; osteomalacia (small subset

pts)pts) SLE

Process-Ludden Plot R (mg/d) vs R/C

(L/d) R1 = 300 mg

phenytoin sodium Both administration

rates (R) must be in h l f

R1/Css1 = 300 mg/d / 8 mg/L = 37.5 L/d

the same salt form: phenytoin sodium or phenytoin acid

R2 = 350 mg phenytoin sodium

phenytoin acid R2/Css2 = 350 mg/d

/ 20 mg/L = 17.5 L/dL/d

Use your calculator to calculate slope (km) and y-intercept (Vmax)

Process

Draw a line thru the 2 points: 400

300 mg/d & 37.5 L/d 350 mg/d & 17.5 L/d 200

300

R

.

m

g

/

d

Y-intercept = Vmax = 393 L/d 100

R

00 20 40

R/Css, L/d

km

[ ][ ]CRCR

RRyslope//

21 == [ ][ ]dmgl

CRCRx ssss/350300

// 2211

[ ][ ]

LkldL

gslope

/52/5.175.37 =

LmgkLmgkslope

m

m

/5.2/5.2

+=+==

gm

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

Please enter your answer Target Css = 14

mg/L/393= dmgV/5.2

/393max==

LmgkdmgV

m

?.???max =+=CkCVSFR +Ckm

Wh t i th t i tWhat is the most convenient dose to give this patient?dose to give this patient?

330 mg/day phenytoin sodium = 3 x 100 mg caps and 1 x 30 mg3 x 100 mg caps and 1 x 30 mg

cap po qd

Recall, linearization of Michaelis-Menten Equation

= +RV Ck C

max

++ =k C

R k C V Ck R C R V C

m

m max( )( )( ) ( )( )+ =

= +k R C R V CC R k R V Cm

m

max

max

( )( ) ( )( )( )( ) ( )( )

= +DivideBothSidesBy CR k R C V

( )( )( / ) +

= +R k R C Vy mx b

m max( )( / )

Solve for Vmax If you plot Vmax vs

km:R k R C Vm= +( )( / ) maxV R k R Cor

in m= + ( / )max VmaxV R C k Ry mx b

m= += +

( / )max Ry mx b= +

Css kmR = y-intercept-C = x-intercept O mCss x intercept

H th l ti hiHow are these relationships used clinically?used clinically?

Mullen MethodMullen Method

Used for two or more [phenytoin]-dose pairs

Orbit Graph Dose AdjustmentOrbit Graph Dose Adjustment

Used if you know a i l t d t tsingle steady-state

[phenytoin] that reflects a knownreflects a known dosing regimen

Orbits represent the fraction of the sample patient population whose kpopulation whose kmand Vmax values are within that orbitSheiner Nomogramg

Use R in phenytoin acid

Requirements

Only for adult patients [Phenytoin] must be an average steady- [Phenytoin] must be an average steady-

state value[Phenytoin] must represent the [Phenytoin] must represent the concentrations you would expect when plasma protein binding conditions areplasma protein binding conditions are normal

Average Steady State [Phenytoin] CAverage Steady-State [Phenytoin] - Css

Important for determining Vmax & kkm

Required when nomograms are usednomograms are used

When to make adjustment: Drug is given qd Ctr < 5 mg/L

Dose > 400 mg/d Dose > 400 mg/d

Average Steady-State [Phenytoin] - Css For intermittent short-term IV infusion Assumes Css is halfway between the Cpk & Ctr

CS F Dose

C +C

VCss

Dtrough= +2

Average Steady-State [Phenytoin] - Css For oral: Based upon the observation of a fluctuation

at steady-state following oral dosing about half ( x = ) that observed with IV administrationadministration

S F Dose C

S F DoseV

CssD

trough= +4

Adjustments for Protein BindingH lb i i Hypoalbuminemia To allow use of total [phenytoin] and the

l th tiusual therapeutic range

CCobservedCSalbnormalobserved= +( . )( ) .0 2 01

Cnormal is the [phenytoin] that would have been observedif the patients serum albumin would have been normal.

Adjustments for Protein BindingR l F il Renal Failure To allow use of total [phenytoin] and the

l th tiusual therapeutic range

CCobservedCSalbnormalbindingobserved= +( . )( ) .01 01

Cnormalbinding is the [phenytoin] that would have been observedif the patients protein binding/affinity would have been normal.g y

Adjustments for Protein Binding

Valproic Acid To allow use of total [phenytoin] and the

usual therapeutic range

( )( )[ ]( )DPHVPAC ingnormalbind 01.095.0 +=Cnormalbinding is the [phenytoin] that would have been observedif the patients protein binding/affinity would have been normal.g y

Pediatric Patients

Patient CasePatient Case

CK is a 60 yo 60 kg female patient with a long h/o tonic-clonic seizure disordera long h/o tonic-clonic seizure disorder moderately well-controlled by phenytoin sodium 300 mg po qd In Seizuresodium 300 mg po qd. In Seizure Clinic, her total [phenytoin] = 5 mg/L with a SCr of 1 3 ml/dl and a serumwith a SCr of 1.3 ml/dl and a serum albumin of 2.0 g/dl. Using the Sheiner nomogram (orbit graph) what are CKsnomogram (orbit graph), what are CK s Vmax & km?

Requirements

Only for adult patients [Phenytoin] must be an average steady- [Phenytoin] must be an average steady

state value [Phenytoin] must represent the[Phenytoin] must represent the

concentrations you would expect when plasma protein binding conditions are normal

R must be in phenytoin acid

Wh t i R ( /k /d) iWhat is R (mg/kg/d) in phenytoin acid?phenytoin acid?

R (mg/kg/d)

Rdailydose S F= ( )( )( )R

Wt

Rmg d= ( / )( . )( . )300 0 92 0 95R

kgR mg kg d

== . . / /

604 37 4 4 g g

Patient is on a once-daily regimen with Patient is on a once daily regimen with [phenytoin] = 5 mg/L

SCr = 1.3 mg/dl; Salb = 2.0 g/dl, wt = 60 kgg/ ; g/ , g Calculate Css Need VD Need VD Patient has hypoalbuminemia:

VD (L/kg) = 2.8/serum albumin (g/dl) x Wt (kg)

S F Dose C

S F DoseV

CssD

trough= +4

Average Steady-State [Phenytoin] - Css

Patient is on a once-daily regimen with y g[phenytoin] = 5 mg/L

SCr = 1.3 mg/dl; Salb = 2.0 g/dl SCr 1.3 mg/dl; Salb 2.0 g/dl

If the patient has hypoalbuminemia:

VD (L/kg) = 2.8/serum albumin (g/dl) x Wt (kg)

VD (L/kg) = 2.8/ 2.0 (g/dl) x Wt (kg) = 84 L

S F DoseC

S F DoseV

CssD

trough= +4C

mgL

mg Lss = +0 92 0 95 3004 84 5( . )( . )( )

( )( )/

C mg Lss = 58. /vs measured phenytoin =5 0 mg/L

Next step: [Phenytoin] must represent the concentrations you

vs. measured phenytoin =5.0 mg/L

represent the concentrations you would expect when plasma protein binding conditions are normalbinding conditions are normal

CCS lbnormalobserved=

( )( )0 2 01Salb

Cmg L

normal +( . )( ) .. /

0 2 0158

C

mg L

normal = +( . )( . ) ./

0 2 2 0 0158

Cmg L

C mg L

normal = . /./

5805

116C mg Lnormal = . /116

Plot

R = 4.4 mg/kg/d C = 11 6 mg/L Css = 11.6 mg/L Vmax = ? Km = ?

mg/kg/d

Km = 5.5 mg/L Vmax = 6.5 mg/kg/d x 60 kg = 390

mg/d What if you want to increase Css to 15

mg/L? V C( )( )g/ Calculate: SFR

V Ck C

mg d mg L

ss

m ss= +

( )( )

( / )( / )

max

390 15SFR

mg d mg Lmg L mg L

mg d

= +=

( / )( / ). / /

/

390 1555 15

2854mg d

Rmg d

mg d

== =

. /. /

( )( ). /

285428540 92 0 95

3265 330( . )( . )0 92 0 95

Or plot: Or plot: Red line crosses y-axis at 5 mg/kg/d

phenytoin acid:phenytoin acid:

k d k( / / )( )R

mg kg d kgmg d mg d= = ( / / )( )

( . )( . )/ /

5 600 92 0 95

343 330

Despite your recommendations, CKs p y ,phenytoin dose is increased to phenytoin sodium capsules 200 mg po bid Si h l CK lbid. Six months later, CKs total [phenytoin] is found to be 18 mg/L and she is demonstrating nystagmus &she is demonstrating nystagmus & ataxia. SCr = 1.0; Salb 2.0Is the [phenytoin] at steady state? Is the [phenytoin] at steady-state?

Use the Mullen method to determine V & kVmax & km.

What are your recommendations at this time?time?

Time to Achieve 90% of SSt

k VV R

V Rm Din

in90% 2 2 3 0 9= ( ) ( . . )max max

tmg L L

mg d mg dmg d mg d90% 2

55 84390 350

2 3 390 0 9 350= . /

( / / )( . ( / ) . ( / )

tmg

mg dmg d mg d90% 2

2

46240

897 315= ( / )

( / / )

t d mg mg dt days months

90%2

90%

0 28875 582168 56

== =

( . / )( / ).

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

Mullen (Cornish-Bowden) MethodMullen (Cornish Bowden) Method

Used for two or more [phenytoin]-dose pairs

Requirements

Only for adult patients [Phenytoin] must be an average steady- [Phenytoin] must be an average steady

state value [Phenytoin] must represent the[Phenytoin] must represent the

concentrations you would expect when plasma protein binding conditions are normal

R must be in phenytoin acid

RecallPhenytoin sodium caps 300 mg po qd

Phenytoin sodium caps200 mg po BIDg p=400 mg/d

R1 = 4.4 mg/kg/d R2 = ? mg/kg/dR1 4.4 mg/kg/d phenytoin acid

R2 ? mg/kg/d phenytoin acid

Ctrough = 5 mg/L Ctrough = 18 mg/Ltrough g/ trough g/

Cnormal = 11.6 mg/L Cnormal = ?

What is R2 (mg/kg/d)?What is R2 (mg/kg/d)?

R2 (mg/kg/d)

Rdailydose S F

2 = ( )( )( )R WtR

mg d

2

400 0 92 0 95= ( / )( . )( . )Rkg

R mg kg d

2

2

6058

== . / /g g2

Calculate C Calculate Css Need VD

Patient has hypoalbuminemia:

V (L/kg) = 2 8/serum albumin (g/dl) x Wt VD (L/kg) = 2.8/serum albumin (g/dl) x Wt (kg)

V (L/kg) 2 8/ 2 0 (g/dl) x 60 (kg) 84 L VD (L/kg) = 2.8/ 2.0 (g/dl) x 60 (kg) = 84 L

CS F Dose

VCss trough= +4VD4

S F DoseC

S F DoseV

CssD

trough= +4C

mgL

mg Lss = +0 92 0 95 2004 84 18( . )( . )( )

( )( )/

C mg Lss = 185. /

Next step: [Phenytoin] must

vs. measured phenytoin =18.0 mg/L

Next step: [Phenytoin] must represent the concentrations you would expect when plasma proteinwould expect when plasma protein binding conditions are normal

CobservedCSalbnormalobserved= +( . )( ) .0 2 01

Cmg L

normal = +. /

( . )( . ) .185

0 2 2 0 01

Cmg L

l

+=

( . )( . ) .. /

0 2 2 0 01185

C

C mg L

normal

normal =./ !

0537 gnormal

Recall

Phenytoin sodium caps 300 mg po qd

Phenytoin sodium caps200 mg po BIDg p=400 mg/d

R1 = 4.4 mg/kg/d in R2 = 5.8 mg/kg/d inR1 4.4 mg/kg/d in phenytoin acid

R2 5.8 mg/kg/d in phenytoin acid

Cnormal = 11.6 mg/L Cnormal = 37 mg/LCnormal 11.6 mg/L Cnormal 37 mg/L

14

10

12

14

R

6

8

10 R,Vmax,mg/kg/d

2

4

6 g g

0

2

-38 -34 -30 -26 -22 -18 -14 -10 -6 -2 2 638 34 30 26 22 18 14 10 6 2 2 6

Css mg/L Km mg/Lss g m g

Interpret Graph

See point where lines intersect Locate on y-axis gives you V Locate on y axis gives you Vmax Locate on x-axis gives you km

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

14

10

12

14

R

6

8

10 R,Vmax,mg/kg/d

2

4

6 g g

0

2

-38 -34 -30 -26 -22 -18 -14 -10 -6 -2 2 6

Css mg/L Km mg/Lss g m g

New Dose

Vmax = 6.8 mg/kg/d, km = 6 mg/L 2 methods: 2 methods:

Use plot (see green line from point of intersection to 15 mg/L): crosses x-axis atintersection 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

New DoseNew Dose

Rearrange the Michaelis-Menten equation: Rearrange the Michaelis Menten equation: SFR = (Vmax)(Css)/km + Css

Use the values obtained from your plot for Use the values obtained from your plot for Vmax = 6.8 mg/kg/d = 408 mg/d Km = 6 mg/Lm g/ SFR = (Vmax)(Css)/km + Css SFR = (408 mg/d)(15mg/L)/6 mg/L+15 ( g/ )( g/ )/ g/

mg/L SFR = 291 mg/d phenytoin acid R = 291 mg/d/(0.92)(0.95) = 333

mg/phenytoin sodium

H l h ld I h ld thHow long should I hold the dose?dose?

t

kCC

C Cmt

o t

=

+ ( ) ln ( )0

tV V

Lmg L

L L

D=

/

( / ) l/

( / / )

max

6 037

37 15t

mg Lg

mg Lmg L mg L

mg d L=

+ ( . / ) ln / ( / / )/ /

6 015

37 15

408 84g

tmg L mg L

mg d Ldays days= + = . / /

. / /.

54 224 9

56 6

What is an appropriate order? What is an appropriate order?

Check free [phenytoin]. Hold phenytoin doses Hold phenytoin doses. Check [phenytoin] q 2 - 3 days to

assess trendsassess trends. Restart phenytoin sodium 330 mg po qd

h [ h ] /when [phenytoin] < 15 mg/L (normalized) or < 7.5 mg/L (observed).

H b t iHow about same scenario using a different method?using a different method?

Ludden Method

Recall

Phenytoin sodium caps Phenytoin sodium capsPhenytoin sodium caps 300 mg po qd

Phenytoin sodium caps200 mg po BID=400 mg/d=400 mg/d

R1 = 262 mg/dphen toin acid

R2 = 350 mg/dphen toin acidphenytoin acid phenytoin acid

Cnormal = 11.6 mg/L Cnormal = 37 mg/L

R1/C = 22.6 L/d R2/C = 9.5 L/d

Process Plot R (mg/d) vs R/C

(L/d) R1 = 262 mg

phenytoin acid Both administration

rates (R) must be in h l f

R1/Css1 = 22.6 L/d R2/Css2 =9.5 L/dthe same salt form:

phenytoin sodium or phenytoin acid

2/ ss2 / R2 = 350 mg

phenytoin acidphenytoin acid

Use your calculator to calculate slope (k ) and y-intercept (V )Use your calculator to calculate slope (km) and y intercept (Vmax)

Process

Draw a line thru the 2 points: 400

262mg/d & 22.6 L/d 350 mg/d & 9.5 L/d 200

300

R

.

m

g

/

d

Y-intercept = Vmax = 413.8 L/d 100

R

00 20 40

R/Css, L/d

km

slope R R R C R Css ss= [ ] / [ / ] [ ]1 2 1 1 2 2slope mg d L dl k L

= [ / ] / [ . . / ]/

262 350 22 6 9 56 7slope km mg L

km mg L= =

=. /

. /6 7

6 7km mg L. /6 7

New doseNew doseV mg dmax . /= 4138k mg L

V Cm . /

( )( )= 6 7

SFRV Ck C

d L

ss

m ss

max( )( )

( / )( / )

= +4138 15

SFRmg d mg L

mg L mg L( . / )( / )

. / /= +

4138 156 7 15

mg dphenytoinacidmg dphenytoinsodium

//

=

286327 g p y

mg dphenytoinsodium/ 330

Questions?

phenytoin pk lecture

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