Upload
stacie-penkova
View
35
Download
1
Embed Size (px)
DESCRIPTION
very comprehensive PK lecture on phenytoin
Citation preview
Phenytoin PKPhenytoin PK
Myrna Y. Munar, Pharm.D., BCPSAssociate ProfessorAssociate Professor
Clickers
Turn clicker on by pressing down menu button Enter you OSU student ID number Enter you OSU student ID number The up/down diagonal arrows button on the left is
the button to SEND your answersTh b i l d li k ff The menu button is also used to turn your clicker off But dont turn it off now
Raise your hand if youre having troubley y g OK, lets begin
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
Get your clicker ready
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?
Get your clicker ready
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?
Get your clicker ready
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
Protein binding change
10?Csstotal
Time
DoseDoseC == // up
totalss fCLCLC == int,
Protein binding change
20
Protein binding change
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
Protein binding change
20
Protein binding change
10
?Cssfree
Time
/C
DoseC freess=
int, CLfreess
Protein binding change
20
Protein binding change
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 ==
Special ConsiderationValproic Acid (VPA)
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
Special ConsiderationValproic Acid (VPA)
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 ==
Special ConsiderationValproic Acid (VPA)
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?