Farmakokinetik klinik

Antikonvulsan

LUSIA ERMAN
1705023
 Phenytoin

PENGGUNAAN KLINIS:

Phenytoin efektif untuk mengatasi serangan primer

maupun sekunder akibat tipe seizure lainya
TERAPEUTIC AND TOXIC CONCENTRATION PHENYTOIN

Range terapi untuk total (terikat=tidak

terikat)konsentrasi serum penitoin adalah 10-20
µ/ml
Umumnya range terapi utuk konsentrasi phenitoin
bebas adalah 1-2 µ/ml
 CLINICAL MONITORING PARAMETER

Tujuan terapi antikonvulsan untuk mengurangi

frekuensi epilepsi dan memaksimalkan kualitas
hidup dengan minimum kerugian dan efek samping
obat
Phenytoin mengikuti farmakokinetik nonlinear , jadi
cukup mudah untuk mencapai konsentrasi toksisk
dengan menukar/ mengubah dosis obat.
 Farmakokinetik Phenytoin

Absorbsi
untuk per oral melalui saluran cerna absorpsi
lambat, T maks nya 3 – 12 jam

Distribusi
Berikatan dengan protein terutama albumin plasma
90 %. Juga terikat kuat pada jaringan syaraf
sehingga kerja nya bertahan lebih lama. Vd = 45 L/
70 kg
metabolisme
Phenytoin dimetabolisme oleh hati ( > 95 % ) . Oleh
sistem enzim CYP2C9, dengan jumlah yang lebih kecil
dimetabolisme oleh CYP2C19 . Sekitar 5 % dari dosis
fenitoin terdapat dalam urin sebagai obat tidak berubah
Eksresi
5 % melalui ginjal dan selebihnya di reabsorbsi kembali
 T ½ = 12 – 36 jam, rata – rata 24 jam utk kebanyakan
pasien
 Cp maks = 3 – 12 jam
 EFFECTS OF DISEASE STATES AND CONDITIONS
ON PHARMACOKINETICS AND DOSING

Pasien dengan sirosis hati atau hepatitis akut akan

mengurangi clereance phenytoin karena kerusakan
hati,
Hilangnya fungsi sel hati mengurangi jumlah yang
tersedia untuk metabolisme obat sehingga
mengurangi clereance
Volume distribusi besar karena kurangnya ikatan
protein plasma
Protein binding is reduced and unbound fraction is
increased due to hypoalbuminemia and/or
hyperbilirubinemia (especially albumin ≤3 g/dL
and/or total bilirubin ≥2 mg/dL).
Pada pasien gangguan fungsi hati dapat ditentukan
with applying the Child-Pugh clinical classification
system to the patient
Klasifikasi Child-Pugh

score 1 2 3
Billirubin <2 2-3 >3
(mg/dL)
Albumin >3,5 2,8-3,5 <2,8
(mg/dl)
asites Tidak ada sedikit sedang
Waktu 1-4’ 4-6’ >6’
protrombi
n time
 CLINICAL USEFULNESS OF UNBOUND PHENYTOIN
CONCENTRATIONS

Example 1 JM is an epileptic patient being treated

with phenytoin. He has hypoalbuminemia

(albumin = 2.2 g/dL) and normal renal function
(creatinine clearance =90 mL/min). His total phenytoin
concentration is 7.5 μg/mL. Assuming that any unbound
concentrations performed by the clinical laboratory will
be conducted at 25°C, compute an estimated normalized
phenytoin concentration for this patient.
Choose appropriate equation to estimate normalized total phenytoin

concentration at the appropriate temperature.

CNormal Binding = C/(0.25 ⋅ Alb + 0.1)

= (7.5 μg/mL) / (0.25 ⋅ 2.2 g/dL + 0.1)

= 11.5 μg/mL

CfEST = 0.1 CNormal Binding

= 0.1 ⋅ 11.5 μg/mL = 1.2 μg/mL

This patient’s estimated normalized total phenytoin concentration is expected to

provide an unbound concentration equivalent to a total phenytoin concentration of
11.5 μg/mL for a patient with normal drug protein binding (CfEST = 1.2 μg/mL).
Cl = Vmax / (Km + C). This is the reason concentrations
increase disproportionately after a phenytoin dosage
increase. For example, phenytoin follows saturable
pharmacokinetics with average Michaelis-Menten
constants of Vmax = 500 mg/d and Km = 4 mg/L. The
therapeutic range of phenytoin is 10–20 μg/mL. As the
steady-state concentration of phenytoin increases from 10
μg/mL to 20 μg/mL, clearance decreases from 36 L/d to
21 L/d:
Cl = Vmax/(Km + C);
Cl = (500 mg/d) / (4 mg/L + 10 mg/L) = 36 L/d;
Cl = (500 mg/d) / (4 mg/L+ 20 mg/L) = 21 L/d
 clearance decreases and half-life becomes longer for the drug:
↑t1/2 = (0.693 ⋅ V) / ↓Cl. Using the above example for
clearance and the volume of distribution for a 70-kg person
(V = 0.7 L/kg ⋅ 70 kg ≈ 50 L),
half-life
changes from 1 d
(t1/2 =[0.693 ⋅ V] / Cl
= [0.693 ⋅ 50 L] / 36 L/d = 1 d)
to 1.7 d
(t1/2 = [0.693 ⋅ 50 L] / 21 L/d = 1.7 d)
as phenytoin serum concentrations increase from 10 μg/mL to
20 μg/mL
 Pharmacokinetic Dosing Method

If the patient has significant hepatic dysfunction

(Child-Pugh score ≥8), maintenance doses computed
using this method should be decreased by 25–50%
depending on how aggressive therapy is required to
be for the individual.
 VOLUME OF DISTRIBUTION ESTIMATE

For example, the volume of distribution for a 70-kg, non obese patient

would equal 49 L (V = 0.7 L/kg ⋅ 70 kg = 49 L). The loading dose to

achieve a total phenytoin concentration of 15 μg/mL is 750 mg [LD =
Css ⋅ V = 15 mg/L ⋅ 49 L = 735 mg, rounded to 750 mg .
For an obese individual with a total body weight of 150 kg and an ideal

body weight of 70 kg, the volume of distribution would equal 123 L:

V = 0.7 L/kg [IBW + 1.33 (TBW − IBW)]

= 0.7 L/kg [70 kg + 1.33(150 kg − 70 kg)] = 123 L.

 Example

TD is a 50-year-old, 75-kg (5 ft 10 in) male with

simple partial seizures who requires therapy with
oral phenytoin. He has normal liver and renal
function. Suggest an initial phenytoin dosage
regimen designed to achieve a steady-state
phenytoin concentration equal to 12 μg/mL.
.
Pharmacokinetic Dosing Method
1. Estimate Michaelis-Menten constants according to disease
states and conditions present in the patient.
The Vmax for a nonobese adult patient with normal liver and renal function
is 7 mg/kg/d. For a 75-kg patient, Vmax = 525 mg/d
: Vmax = 7 mg/kg/d ⋅ 75 kg = 525 mg/d.
For this individual, Km = 4 mg/L.
.
2. Compute dosage regimen.Oral phenytoin sodium capsules
will be prescribed to this patient (F = 1, S = 0.92). The initial dosage interval
(τ) will be set to 24 hours. The dosage equation for phenytoin is
MD= Vmax . Css/ S(Km+Css)
=525 mg/d .12 mg/ L/o,92(4mg/L+12mg/L)=428 mg/d rounded to 400
mg/d
 CARBAMAZEPIN

PENGUNAAN KLINIS
Obat ini digunakan sebagai agent propilaktik utama
pada terapi epilepsi kronik. Carbamazepin juga
digunakan sebagai agen trigeminal dan gangguan
afektif bipolar.
THERAPEUTIC AND TOXIC CONCENTRATIONS

therapeutic range for carbamazepine is 4–12 μg/mL

when the drug is used for the treatment of seizures
Ikatan protein plasma Carbamazepin sangat berbeda
pada tiap individu karena ikatan antara both
albumin and α1-acid glycoprotein (AGP)
In patients with normal concentrations of these
proteins, plasma protein binding is 75–80%
resulting in a free fraction of drug of 20–25%.
In patients with these disease states, such as trauma,
heart failure, and myocardial infarction
carbamazepine binding to AGP can be even larger
resulting in an unbound fraction as low as
10–15%.
In the upper end of the therapeutic range (>8
μg/mL) some patients will begin to experience the
concentration-related adverse effects of
carbamazepine treatment: nausea, vomiting,
lethargy, dizziness, drowsiness, headache, blurred
vision, diplopia, unsteadiness, ataxia, incoordination
 CLINICAL MONITORING PARAMETERS

The goal of therapy with anticonvulsants is to reduce

seizure frequency and maximize quality of life with a
minimum of adverse drug effects
BASIC CLINICAL PHARMACOKINETIC PARAMETERS

Carbamazepine is primarily eliminated by hepatic

metabolism (>99%) mainly via the CYP3A4 enzyme
system.
Carbamazepin berpotensi menginduksi oleh obat
yang memetabolisme enzim hati.
 EFFECTS OF DISEASE STATES AND CONDITIONS
ON PHARMACOKINETICS AND DOSING

Patients with liver cirrhosis or acute hepatitis have reduced

carbamazepine clearance because of destruction of liver
parenchyma. This loss of functional hepatic cells reduces the
amount of CYP3A4 yang tersedia untuk metabolisme obat
sehingga terjadi penurunan clearance.
volume of distribution tinggi karena berkurangnya ikatan
protein plasma.
Ikatan protein mungkin berkurang dan tidak berikatan,
peningkatan hypoalbuminemia and/or hyperbilirubinemia
(especially albumin ≤3 g/dL and/or total bilirubin ≥2 mg/dL).
An index of liver dysfunction can be gained by applying the
Child-Pugh clinical classification system to the patient
Estimate carbamazepine dose according to disease states and conditions present

in the patient. The suggested initial dosage rate for carbamazepine suspension in a

child in this age range is 10–20 mg/kg/d. Using a dose of 15 mg/kg/d, the target

maintenance dose equals 300 mg/d (15 mg/kg/d ⋅ 22 kg = 330 mg/d, rounded to

300 mg/d). The starting dose would be 1/4–1/3 of the target maintenance dose or

100 mg/d given as 50 mg twice daily. This dose would be titrated upward in 100

mg/d increments every 2–3 weeks while monitoring for adverse and therapeutic

effects. The goal of therapy includes maximal suppression of seizures, avoidance of

side effects, and a target drug range of 300 mg/d given as 100 mg three times daily.
 VALPROIC ACID

Valproic acid is an agent that is chemically related to

free fatty acids and is used in the treatment of
generalized, partial, and absence (petit mal) seizures
valproic acid can be used for the acute treatment and
chronic prophylaxis of seizures.
THERAPEUTIC AND TOXIC CONCENTRATIONS

Umumnya range terapi valproic acid konsentrasi

steady state adalah 50- 100 μg/mL,
Valproic acid banyak berikatan dengan protein
albumin 90–95%.
BASIC CLINICAL PHARMACOKINETIC PARAMETERS

Valproic acid di eliminasi oleh metabolisme hati (>95%).

Hepatic metabolism is via metabolisme hati melalui
glucuronidation, β-oxidation, and α-hydroxylation.

About 1–5% valproic acid dikeluarkan kembali melalui urin

sebagai obat yang tidak diubah.

Valproic acid volume of distribution (V = 0.15 − 0.2 L/kg)

is also affected by concentration-dependent plasma protein
binding and is determined by the physiologic volume of blood
(VB) and tissues (VT) as well as the unbound fraction of drug in
the blood (fB) and tissues (fT): V = VB + (fB/fT)VT.
Half-life (t1/2) is related to clearance and volume of distribution using the

same equation as for linear pharmacokinetics: t1/2 = (0.693 ⋅ V) / Cl

The typical maintenance dose for valproic acid is 15 mg/kg/d resulting in

1000 mg or 500 mg twice daily for most adult patients.

valproic acid pharmacokinetics, many clinicians recommend the

administration of 7.5 mg/kg/d for adults or 10 mg/kg/d for children under 12

years of age receiving monotherapy and 15 mg/kg/d for adults or 20 mg/kg/d

for children under 12 years of age receiving other drugs that are enzyme

inducers.
 EFFECTS OF DISEASE STATES AND CONDITIONS
ON PHARMACOKINETICS AND DOSING

For valproic acid, oral clearance (Cl/F) is 7–12

mL/h/kg and half-life is 12–18 hours for adults
In children 6–12 years old, oral clearance 10–20
mL/h/kg and half-life 6–8 hours
Clearance rates can be higher and half-lives shorter
in patients receiving other hepatic drug–
metabolizing enzyme inducers (phenytoin,
phenobarbital, carbamazepine)
Patients with liver cirrhosis or acute hepatitis have reduced
valproic acid clearance because of destruction of liver
parenchyma
Valproic acid clearance in patients with liver disease is 3–4
mL/h/kg. The volume of distribution may be larger because
of reduced plasma protein binding (free fraction ≈29%)
half-life for valproic acid in patients with liver disease is 25
hours
patient with liver disease to have relatively normal or grossly
abnormal valproic acid clearance and volume of distribution
INITIAL DOSAGE DETERMINATION METHODS

CLEARANCE ESTIMATE
asam valproic dimetabolisme oleh hati,
memperkirakan Valproic acid is predominately
metabolized by liver. Unfortunately, there is no good
way to estimate the elimination characteristics of
liver metabolized drugs using an endogenous marker
of liver function in the same manner that serum
creatinine and estimated creatinine clearance are
used to estimate the elimination of agents that are
renally eliminated.
example,
for a 70-kg adult patient with liver cirrhosis or acute
hepatitis, valproic acid clearance would be assumed
to equal 3–4 mL/h/kg:
= 70 kg ⋅ 3.5 mL/h/kg
= 245 mL/h or 0.245 L/h.
VOLUME OF DISTRIBUTION ESTIMATE

Valproic acid volume of distribution is assumed to equal 0.15 L/kg for adults and 0.2 L/kg

for children under 12 years of age. Thus, for an 80-kg adult patient, the estimated valproic

volume of distribution would be 12 L: V = 0.15 L/kg ⋅ 80 kg = 12 L. Patients with cirrhosis or

renal failure may have larger volumes of distribution as a result of decreased plasma protein

binding.

HALF-LIFE AND ELIMINATION RATE CONSTANT ESTIMATE

Once the correct clearance and volume of distribution estimates are identified for the patient,

they can be converted into the valproic acid half-life (t1/2) and elimination rate constant (k)

estimates using the following equations: t1/2 = (0.693 ⋅ V) / Cl, k = 0.693/t1/2 = Cl/V
 EXAMPLE

Example 1 KL is a 51-year-old, 75-kg (5 ft 10

in) male with tonic-clonic seizures who
requires therapy with oral valproic acid. He has
normal liver function and takes no medications that
induce hepatic enzymes. Suggest an initial valproic
acid dosage regimen designed to achieve a steady-
state valproic acid concentration equal to 50 μg/mL.
1. Estimate clearance and volume of distribution
according to disease states and conditions
present in the patient. The clearance rate for an adult patient
not taking other drugs that induce hepatic drug metabolism is
7–12 mL/h/kg. Using a value of 10 mL/h/kg, the estimated
clearance would equal 0.75 L/h:
Cl = 75 kg ⋅ 10 mL/h/kg
= 750 mL/h or 0.75 L/h. Using 0.15 L/kg, the estimated
volume of distribution would be 11 L:
75 kg ⋅ 0.15 L/kg = 11 L.
2. Estimate half-life and elimination rate constant.

Once the correct clearance and volume of distribution estimates are identified
for the patient, they can be converted into the valproic acid half-life (t1/2) and
elimination rate constant (k) estimates using the following equations:
t1/2 = (0.693 ⋅ V) / Cl
= (0.693 ⋅ 11 L) / 0.75 L/h
= 10 h,
k = 0.693/t1/2
= 0.693/10 h
= 0.069 h−1.
3. Compute dosage regimen.

Oral enteric-coated divalproex sodium tablets will be prescribed to this patient (F = 1). (Note:

μg/mL = mg/L and this concentration unit was substituted for Css in the calculations so that

unnecessary unit conversion was not required.) The dosage equation for oral valproic acid is

D = (Css ⋅ Cl ⋅ τ) / F = (50 mg/L⋅ 0.75 L/h ⋅ 12 h) / 1

= 450 mg, rounded to 500 every 12 hours.

A steady-state trough valproic acid serum concentration should be measured after steady

state is attained in 3–5 half-lives. Since the patient is expected to have a half-life equal to 10

hours, the valproic acid steady-state concentration could be obtained any time after the

second day of dosing (5 half-lives = 5 ⋅ 10 h = 50 h).