Therapeutic Drug Monitoring

of
Carbamazepine
Struktur Carbamazepine
• Carbamazepine adalah obat antikonvulsan
yang secara struktur sama dengan
antidepresan trisiklik dan digunakan dalam
pengobatan generalized tonic-clonic, partial,
and partial-complex seizures.

• Obat ini digunakan terutama sebagai agen

pencegahan dalam terapi epilepsi kronis.
• Carbamazepine juga digunakan dalam
pengobatan trigeminal neuralgia and bipolar
affective disorders.

• Efek farmakodinamik carbamazepine memiliki

korelasi yg lebih baik dengan konsentrasi
serum atau plasma dibandingkan dengan dosis
obat.
• Aktivitas antiseizure carbamazepine
berhubungan dengan kemampuannya untuk
menurunkan transmisi dalam bagian nucleus
ventralis anterior dari thalamus, sebuah area
di otak yang diperkirakan terlibat dalam faktor
pemicu dan perambatan epileptic.
• Mekanisme kerja dari carbamazepine diduga dengan
cara menstabilisasi kondisi inactive dari voltage-
gated sodium channels pada otak. Hasilnya adalah
sel-sel otak menjadi lebih susah terangsang, dan
aktivitas seizure berkurang.

• Efek negative (adverse effect) dari level obat yg

melebihi level terapetik optimum berupa hilangnya
kemampuan koordinasi, drowsiness (kantuk), dan
arrhythmia.
 THERAPEUTIC AND TOXIC
CONCENTRATIONS
• Rentang terapi carbamazepine yang digunakan
untuk perawatan seizures adalah 4–12 μg/mL
• Ikatan Carbamazepine dan plasma protein
cukup bervariasi antar individu karena ia terikat
baik dengan albumin maupun α1-acid
glycoprotein (AGP).
• Pada pasien yang memiliki konsentrasi normal
protein, ikatan plasma protein 75–80% dengan
fraksi obat bebas sebesar 20–25%
• Pada pasien yang mengalami trauma, gagal
jantung dan myocardial infarction,
carbamazepine terikat dengan AGP dalam
jumlah yang lebih besar hingga fraksi obat
bebas dapat menurun hingga 10–15%.
• Carbamazepine-10, 11-epoxide adalah metabolit
aktif dari carbamazepine yang berkontribusi baik
pada efek terapetik maupun toksik dari
carbamazepine.
• Konsentrasi epoxide sering terkait dengan ada atau
tidaknya inhibitors atau penginduksi lain pada
enzym-enzym metabolik di hati.
• Konsentrasi Epoxide cenderung meninggi pada
pasien yg juga mendapatkan penginduksi enzyme
dan lebih rendah jika bersama enzyme inhibitors.
• Saat ini, range terapi carbamazepine-10, 11-
epoxide tidak diketahui walaupun beberapa
pusat penelitian menyarankan range antara
0.4–4 μg/mL.
• Pada range batas atas dari therapeutic range (>8
μg/mL) beberapa pasien akan mulai mengalami
efek samping: nausea, vomiting, lethargy,
dizziness, drowsiness, headache, blurred vision,
diplopia, unsteadiness, ataxia, incoordination
• Efek samping ini juga terlihat segera selama
masa titrasi dosis jika dilakukan peningkatan
dosis.
• Untuk meningkatkan penerimaan pasien,
penting untuk memulai dan mentitrasi dosis
carbamazepin pada kecepatan rendah untuk
meminimalisasi efek samping.
 CLINICAL MONITORING PARAMETERS
• Tujuan terapi antikonvulsan adalah untuk
mengurangi frekuensi seizure dan memaksimalkan
kualitas hidup dengan efek samping yang minimum.
• Pasien harus dimonitor terhadap efek samping
terkait konsentrasi (nausea, vomiting, lethargy
(lesu), dizziness (pusing), drowsiness, headache,
blurred vision (kabur), diplopia (double vision),
unsteadiness (goyang), ataxia (kehilangan
keseimbangan), incoordination)
• Beberapa pasien dapat mengalami hyponatremia selama
terapi kronik dengan carbamazepine, dan konsentrasi
serum sodium sebaiknya diukur secara periodik.
• Efek samping hematologis terbagi atas 2 tipe:
1. Leukopenia,( a normal white blood cell count who
develops a transient decrease in this index). tak
memerlukan intervensi terapetik.
2. Thrombocytopenia (white blood cell count with <2500
cells/mm2 or absolute neutrophil count <1000
cells/mm2). Perlu penghentian pengobatan.
• Efek samping hematologic dan hepatic yang
berat kebanyakan terjadi pada awal terapi.
• Karena itu, Clinicians mengukur a complete
blood cell count and liver function tests setiap
bulan pada 3–6 bulan pertama setelah pasien
mulai menerima pengobatan carbamazepine
treatment,dan diulangi setiap 3–6 bulan untuk
tahun pertama.
 BASIC CLINICAL PHARMACOKINETIC
PARAMETERS
• Carbamazepine is primarily eliminated by
hepatic metabolism (>99%) mainly via the
CYP3A4 enzyme system.
• Carbamazepine is a potent inducer of hepatic
drug metabolizing enzymes, and induces its
own metabolism, a process known as
autoinduction.
• At first, patients are started on 1/4–1/3 of the
desired maintenance dose.
• This exposes hepatic drug metabolizing
enzymes to carbamazepine and begins the
induction process.
• The dose is increased by a similar amount
every 2–3 weeks until the total desired daily
dose is ultimately given.
• This gradual exposure of carbamazepine
allows liver enzyme induction and
carbamazepine clearance increases to occur
over a 6- to 12-week time period.
• Therapeutic effect and steady-state
carbamazepine serum concentrations can be
assessed 2–3 weeks after the final dosage
increase.
• An injectable form of carbamazepine is not
available.
• For oral use, the drug is available as
immediate-release tablets (chewable: 100 mg,
regular: 100 mg, 200 mg, 300 mg), sustained-
release tablets (100 mg, 200 mg, 400 mg),
sustained-release capsules (100, 200,300 mg),
and suspension (100 mg/5 mL).
• The rapid release dosage forms are erratically
absorbed from the gastrointestinal tract
resulting in peak concentrations between 2–24
hours after a single dose of tablets (average 6
hours)
• During multiple dose studies after maximal
autoinduction has taken place, peak
concentrations occur about 3 hours after tablet
administration.
• Peak concentrations after multiple doses of
the sustained-release dosage forms are
observed 3–12 hours after administration.
• Rectal administration of an extemporaneously
compounded carbamazepine retention enema
results in similar serum concentrations as that
produced by a comparable immediate-release
tablet.
• The absolute oral bioavailability of
carbamazepine is not known because no
intravenous form of the drug is available for
comparison.
• Based on the best estimates available,
carbamazepine bioavailability is good and
averages about 85–90%.
• Usual initial maintenance doses are 10–20 mg/kg/d for
children under 6 years of age, 200 mg/d for children 6–12
years old and 400 mg/d for adults.
• Twice daily dosing is initially used until autoinduction takes
place.
• Dosage increases to allow for autoinduction are made
every 2–3 weeks depending on response and adverse
effects.
• Most adults will require 800–1200 mg/d of carbamazepine
while older children will require 400–800 mg/d
• Although some minor side effects occur, single
loading doses of 8 mg/kg have been given to
adults as suspension or immediate-release
tablets in order to achieve therapeutic
concentrations within 2–4 hours after
administration.
EFFECTS OF DISEASE STATES AND CONDITIONS
ON PHARMACOKINETICS AND DOSING
• After single doses of carbamazepine, the oral
clearance (Cl/F) is 11–26 mL/h/kg and halflife is 35
hours for adults.
• During multiple dosing after maximal autoinduction
has taken place, oral clearance equals 50–100
mg/h/kg and half-life equals 5–27 hours.
• In children 6–12 years old, oral clearance and half-
life equal 50–200 mL/h/kg and 3–15 hours,
respectively, during chronic dosing
• Clearance rates can be higher and half-lives
shorter in patients receiving other hepatic
drug metabolizing enzyme inducers
(phenytoin, phenobarbital, rifampin).
• Carbamazepine volume of distribution using
immediate release tablets (V/F) is 1–2 L/kg
• 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 available to metabolize the drug
and decreases clearance.
• Carbamazepine serum concentrations and the
presence of adverse drug effects should be
monitored frequently in patients with liver cirrhosis.
• Elderly patients have lower carbamazepine oral
clearance rates than younger adults so lower initial
doses (100 mg/d) may be used in older individuals.
• During the third trimester of pregnancy, oral
clearance of carbamazepine may decrease and
require dosage adjustment.
• Doses of carbamazepine do not require adjustment
for patients with renal failure, and the drug is not
removed by dialysis.
 DRUG INTERACTIONS
• Carbamazepine is a potent inducer of hepatic
drug metabolizing enzyme systems and P-
glycoprotein.
• The CYP1A2, CYP2C9, and CYP3A4 enzyme
systems are all induced by carbamazepine,
and drug substrates for other enzyme systems
also have known drug interactions with
carbamazepine.
• Other antiepileptic drugs that have their clearance rates
increased and steady-state concentrations decreased by
carbamazepine-related enzyme induction include
felbamate, lamotrigine, phenytoin, primidone, tiagabine,
topiramate, and valproic acid.

• Carbamazepine therapy also increases the clearance and

decreases steady-state concentrations of many other
drugs including oral contraceptives, calcium channel
blockers, tricyclic antidepressants, cyclosporin, tacrolimus,
theophylline, and warfarin.
• As a general rule, when carbamazepine is
added to a patient’s drug regimen, loss of
therapeutic effect of one of the other drugs
the patient is taking must be considered as a
possible drug interaction with carbamazepine.
• Phenytoin and phenobarbital can increase
carbamazepine clearance and decrease
carbamazepine steady-state serum concentrations.
• Cimetidine, macrolide antibiotics, azole
antifungals, fluoxetine, fluvoxamine, nefazodone,
cyclosporine, diltiazem, verapamil, indinavir, and
ritonavir are examples of drugs that decrease
carbamazepine clearance and increase
carbamazepine steady-state concentrations
• Administration of single doses of
carbamazepine with grapefruit juice increases
both the area under the serum concentration
versus time curve (AUC) and maximal serum
concentration (Cmax) of carbamazepine by
about 40%.
 General Dosing
• the expected carbamazepine steady-state
serum concentrations used to compute these
doses was 6–8 μg/mL.
• Usual initial maintenance doses are 10–20
mg/kg/d for children under 6 years of age, 200
mg/d for children 6–12 years old and 400 mg/d
for adults.
• Twice daily dosing is initially used until
autoinduction takes place.
• Dosage increases to allow for autoinduction
are made every 2–3 weeks depending on
response and adverse effects.
• Most adults will require 800–1200 mg/d of
carbamazepine while older children will
require 400–800 mg/d.
• Contoh Soal:
• KL adalah seorang pria berumur 51 thn, berat
75-kg dengan penyakit simple partial seizures
yg membutuhkan terapi oral carbamazepine.
Dia memiliki fungsi hati normal. Sarankanlah
regimen dosis initial carbamazepine yg
dirancang utk mencapai konsentrasi steady-
state carbamazepine 6–8 μg/mL.