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FARMAKOKINETIKA KLINIK
ANTIBIOTIKA AMINOGLIKOSIDA
Arief Rahman Hakim
arief.h1@gmail.com

PENDAHULUAN
Aminoglikosida :
Bactericidal, treatment serious gram-negative
infections
Absorption from GI is poor parenterally (by
intermittent iv infusion)
Pemilihan dosis dipengaruhi oleh : specific agent (spt
gentamicin vs amikacin), infection (spt site and
organism), renal function, dan weight or body
composition patient
Most commonly monitored : gentamicin, tobramycin,
and amikacin

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PENDAHULUAN
Usual dose :
Gentamicin and tobramycin : 50-120 mg (1-2
mg/kg), diberikan selama 30-60 menit dengan
interval dosis tiap 8 jam
Amikacin : 200-500 mg (5-7,5 mg/kg) tiap 8-12
jam

Cl, Vd, t1/2 similar, model farmakokinetika

yang sama dapat digunakan untuk semua
aminoglikosida

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KONSENTRASI PLASMA TERAPETIK &

TOKSIK
Peak Cp (Cpss max) gentamicin & tobramycin : 48 mg/L
Cp <2-4 mg/L (trough Cp, Cpss min) ineffective
Cp 8 mg/L successful treatment of pneumonia

Peak Cp amikacin : 20-30 mg/L, trough Cp : <10

mg/L
Correlating aminoglikosida concentrations with
oto- and nephrotoxicity refer to trough Cp
Most patient develop renal dysfunction during
terapi aminoglikosida appear to regain normal
renal function after the drug discontinued

KONSENTRASI PLASMA TERAPETIK &

TOKSIK
Ototoxicity associated with Cpss min
gentamicin >4 mg/L selama lebih dari 10 hari
Standard practice to use Cp aminoglikosida as
predictors for both efficacy and toxicity

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BIOAVAILABILITAS (F)
Antibiotika aminoglikosida very water
soluble and poorly lipid soluble
Poorly absorbed when administered orally and
must be administered parenterally for the
treatment of systemic infections
F=1
S=1

VOLUME DISTRIBUSI (Vd)

Vd = 0,25 L/kg, relatively wide range 0,1-0,5
L/kg reported
Vd untuk pasien obese = (0,25 L/kg)(IBW) +
0,1 (TBW-IBW)
Vd increased in patient with ascites, edema, or
other enlarged third space volume
Asumsi Vd approximately equal to the
extracelluar fluid volume

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VOLUME DISTRIBUSI (Vd)

Vd untuk pasien dengan third space volume
Vd (L) = (0,25 L/kg *non-obese, non-excess fluid weight
(kg)) + 0,1*(excess adipose weight (kg)) + (excess third
space fluid weight (kg)
Non-obese, non-excess fluid weight = IBW
Excess adipose weight = TBW-IBW (tanpa excess third-space
fluid)
Excess third-space fluid weight = difference between the
initial and current weight

One-compartment model is generally assumed

for aminoglikosida farmakokineka calculation

Klirens (Cl)
Eliminasi aminoglikosida almost entirely by the
renal route
Since aminoglikosida and ClCr are similar over a
wide range of renal function, Cl aminoglikosida
can be estimated from the formula used to
estimate ClCr when Cp within the therapeutic
range
Correct estimate of ClCr can only be obtained if
the patients weight represents a normal ratio of
muscle mass to TBW, and serum creatinine at
steady state

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KLIRENS KREATININ (ClCr)

ClCr ( pria ) (mL / menit )

(140 umur )( BB )
(72)( SCr )

ClCr ( wanita ) (mL / menit ) (0,85)

(140 umur )( BB )
(72)( SCr )

Umur dalam tahun; BB dalam kg; SCr dalam mg/dL

Pasien obesitas & have third-space fluid BB menggunakan IBW

TBW, IBW, LBW

TBW (total body weight), IBW (ideal body
weight), LBW (lean body weight)
Anonim (2008) & Green & Duffull (2004) :
Pasien dengan TB 150 cm (TB dlm cm & BB dlm
kg) :
IBW pria dewasa = 50 kg + [0,9 kg x (TB-150)]
IBW wanita dewasa = 45 kg + [0,9 kg x (TB-150)]
LBW = IBW + 1/3 x (TBW-IBW)

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Klirens (Cl)
Cl untuk morbidly obese (BB = 2*IBW)
BB = IBW + 0,4*(TBW-IBW)

Another factor which should be considered when

estimating Cl aminoglikosida non-renal Cl =
0,0021 L/kg/jam (= 2,5 mL/menit/70 kg)
Non-renal Cl generally ignored in most patient,
but it significant in patient whose renal function
is markedly diminished
Anephric and on intermittent hemodialysis patient
Cl = 0,0043 L/kg/jam (5 mL/menit/70 kg) represents
the residual renal klirens as well as non-renal klirens

Klirens (Cl)
Carbenicillin, ticarcillin, and related extended spectrum
penicillins inactivate gentamicin and tobramycin in
vitro
Clinically significant in vivo in patients with renal failure
This interaction function of the specific aminoglikosida, the
penicillin compound, the concentration of the penicillin
compound, and temperature

Amikacin much less likely to interact with these

penicillins
Cl Tobramycin, Gentamicin by Carbenicillin (L/jam) =
(0,017/jam)*(Vd aminoglikosida)

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WAKTU PARO ELIMINASI (t1/2)

0,693

1/2 =

Since renal function varies considerably among

individuals, t1/2 also variable
Contoh :

Pria, 70 kg, 25 tahun dengan SCr 0,8 mg/dL Cl

aminoglikosida = 100 mL/menit, bila Vd 0,25 L/kg t1/2 =
2 jam
Pria, 75 tahun, Vd sama, SCr 1,4 mg/dL Cl aminoglikosida
= 35 mL/menit, t1/2 = 6 jam

Initial aminoglikosida dose and dosing interval should

be selected with care

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TIME TO SAMPLE
Correct timing of the sample collection
important, because aminoglikosida have a
relatively short half-life and small but significant
distribustion phase
Peak Cp be obtained one hour after the DM
initiated, assume drug infused over about 30
minutes (acceptable the infusion period 20-40
minutes)
Trough Cp should be obtained within the halfhour (setengah jam) before the administration of
the next DM

TIME TO SAMPLE
Cp clinical peak which one hour after start infusion :

0 =

Optimal time to sample within first 24 hours therapy

difficult to determine
Standard practice to obtain the first aminoglikosida
sample after three or four doses administered,
majority patient approching steady state by this time.
When aminoglikosida administered IM, time aborption
less predictable; Cp max about one hour after IM
injection Cp max should be obtained in this time

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PERSAMAAN
When duration infusion or absorption less
than one-sixth of half-live (<1/6*t1/2)
bolus dose model can be used :

Cp1 =

( 1 )

PERSAMAAN
If duration drug input greater than one-half of
half-live (>1/2*t1/2) the short infusion
model used :
Cp2 =

(1 )( 2 )

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PERSAMAAN
In patient with decreased renal function and
longer aminoglikosida half-live bolus dose
model could be used satifactory
In patient with good renal function (yi young
adults and children), use infusion model is
more appropriate, because have very short
aminoglikosida half-live

PERSAMAAN
If bolus dose model applied, used to predict
the peak levels steady state :
1 =

( 1 )

t1= time interval between start infusion and time

at peak concentration sample
= interval between dose

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PERSAMAAN
Trough concentration (Cpss min) at steady
state :

Cpss min =

( )

= interval between dose

PERSAMAAN
If infusion model used :
=

(1 )

tin= duration infusion

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PERSAMAAN
Intermittent infusion steady state model :

Cpss2 =

= dosing interval,
t2 = time interval between the end infusion and
time at concentration measured

PERSAMAAN
Intermittent infusion steady state model
trough concentration at steady state :
Cpss min =

( )

= dosing interval,
t2 = time interval between the end infusion and
time at concentration measured = -tin

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PERSAMAAN
Intermittent infusion steady state model
trough concentration can also calculated :
Cpss min = (Cp0)(e-kt)
Cp0 = Cpss max
t = time from peak concentration to time of
trough sampling

PERSAMAAN
To calculate DM untuk model infus iv:
DM =

(2 )(1 )

(1 )( 2 )

2*t1/2 atau lebih

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PERSAMAAN
To calculate DM untuk model iv bolus:
DM =

(1 )()(1 )
()()( 1 )

2*t1/2 atau lebih

PERSAMAAN
To calculate Cl bila ada TDM at steady state :
Cl =

( 2 )

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TUGAS KELOMPOK
Kirimkan email ke arief.h1@gmail.com untuk minta
materi kuliah dan tugas kelompok dengan menyebut
nama, no mhs, kelompok berapa dan FKK berapa
Analisis kasus-kasus berikut, bagilah untuk semua
anggota kelompoknya
Laporan kelompok dikirimkan via email dengan
memberikan nama file laporan : kelompok berapa FKK
berapa
Laporan kelompok diserahkan paling lambat hari Kamis
tanggal 18 Desember 2014 pukul 23:59:59 WIB

Kasus 1
R.W., 30 tahun, 70 kg, wanita dengan serum
kreatinin 0,9 mg/dL. Diberikan gentamicin
dengan dosis awal 100 mg secara infus iv
selama 30 menit. Hitunglah konsentrasi
plasma gentamicin 1 jam setelah infus iv
dimulai.
Bila gentamisin diberikan tiap 8 jam, hitunglah
konsentrasi tunak plasma maksimum dan
minimum gentamisin

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Kasus 2
L.K., 40 tahun, 50 kg, wanita dengan serum kreatinin 1
mg/dL diberikan tobramycin. Tentukan dosis
pemeliharaan dan interval dosis tobramycin yang dapat
menghasilkan konsentrasi maksimum tunak 7 mg/L
satu jam setelah infus iv dimulai dan konsentrasi
minimum tunak <2 mg/L. Tobramycin diberikan infus iv
selama 0,5 jam.
Bila L.K. Diberikan tobramycin 5 mg/kg sekali sehari
secara infus iv selama 30 menit, hitunglah konsentrasi
tunak maksimum (satu jam setelah infus dimulai),
konsentrasi tunak 12 jam setelah pemberian, dan
konsentrasi tunak minimalnya.

Kasus 3
Y.B., 70 kg, 38 tahun dengan serum kreatinin 1,8
mg/dL, diberikan infus iv tobramycin 100 mg selama
0,5 jam, 3 kali sehari untuk beberapa hari. Konsentrasi
maksimum plasma satu jam setelah infus dimulai 8
mg/L, dan konsentrasi minimalnya sesaat sebelum
dosis berikutnya diberikan 3 mg/L. Estimasikan harga
konstanta kecepatan eliminasi, klirens, dan volume
distribusi tobramycin pada pasien tersebut
Rekomendasikan regimen dosis untuk pasien Y.B. Agar
dapat menghasilkan konsentrasi maksimum tunak 7
mg/L dan minimal tunaknya <2 mg/L

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Kasus 4
D.H., 40 tahun, pria dibawa ke UGD. Pasien
memiliki tinggi badan 165 cm dan saat masuk
UGM BB 85 kg. Pasien akan menjalani operasi
abdominal dan setelah operasi mengalami
hipotensi dan diberikan cairan infus dengan
volum besar untuk menjaga tekanan darahnya.
Saat ini, BB nya 105 kg dan serum kreatininnya 2
mg/dL. D.H. Menerima gentamicin sebagai terapi
empiris paska operasi abdominal.
Rekomendasikan regimen dosis gentamisin agar
dapat menghasilkan konsentrasi tunak
maksimum 5-7 mg/L dan minimum <2 mg/L.

Kasus 5
D.L., umur 38 tahun, 70 kg, riwayat gagal ginjal
diberikan gentamicin dan carbenicillin.
Rekomendasikan regimen dosis gentamicin
untuk pasien tersebut agar dapat
menghasilkan konsentrasi tunak maksimal 8
mg/L dan minimal <2 mg/L.

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Kasus 6
T.C. Diberikan tobramycin 120 mg secara infus
iv selama 30 menit tiap 8 jam, yaitu pada jam
1:00, 9:00, dan 17:00. Konsentrasi tunak
tobramycin diukur pada jam 8:30 dan 11:30
dihasilkan kadarnya berturut-turut 0,9 mg/L
dan 3,9 mg/L. Hitunglah konsentrasi tunak
maksimal tobramycin pada jam 10:00 (satu
jam setelah infus dimulai).

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