13/12/2014FARMAKOKINETIKA KLINIK ANTIBIOTIKA AMINOGLIKOSIDA Arief Rahman Hakim [email protected] 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 1 t1/2 similar. Vd. diberikan selama 30-60 menit dengan interval dosis tiap 8 jam – Amikacin : 200-500 mg (5-7. model farmakokinetika yang sama dapat digunakan untuk semua aminoglikosida 2 .5 mg/kg) tiap 8-12 jam • Cl.13/12/2014 PENDAHULUAN • Usual dose : – Gentamicin and tobramycin : 50-120 mg (1-2 mg/kg). 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 3 .13/12/2014 KONSENTRASI PLASMA TERAPETIK & TOKSIK • Peak Cp (Cpss max) gentamicin & tobramycin : 48 mg/L – Cp <2-4 mg/L (trough Cp. trough Cp : <10 mg/L • Correlating aminoglikosida concentrations with oto. Cpss min) ineffective – Cp 8 mg/L successful treatment of pneumonia • Peak Cp amikacin : 20-30 mg/L. edema.13/12/2014 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)(IBW) + 0.1-0.5 L/kg reported • Vd untuk pasien obese = (0.25 L/kg. relatively wide range 0.1 (TBW-IBW) • Vd increased in patient with ascites. or other enlarged “third space” volume • Asumsi Vd approximately equal to the extracelluar fluid volume 4 . non-excess fluid weight (kg)) + 0.13/12/2014 VOLUME DISTRIBUSI (Vd) • Vd untuk pasien dengan “third space” volume Vd (L) = (0.25 L/kg *non-obese. 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 patient’s weight represents a normal ratio of muscle mass to TBW. and serum creatinine at steady state 5 .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. LBW • TBW (total body weight).85) (140 umur )( BB ) (72)( SCr ) Umur dalam tahun.9 kg x (TB-150)] • IBW wanita dewasa = 45 kg + [0. IBW.9 kg x (TB-150)] • LBW = IBW + 1/3 x (TBW-IBW) 6 .13/12/2014 KLIRENS KREATININ (ClCr) ClCr ( pria ) (mL / menit ) (140 umur )( BB ) (72)( SCr ) ClCr ( wanita ) (mL / menit ) (0. IBW (ideal body weight). BB dalam kg. 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. SCr dalam mg/dL Pasien obesitas & have third-space fluid BB menggunakan IBW TBW. but it significant in patient whose renal function is markedly diminished – Anephric and on intermittent hemodialysis patient Cl = 0. 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. Gentamicin by Carbenicillin (L/jam) = (0.017/jam)*(Vd aminoglikosida) 7 .4*(TBW-IBW) • Another factor which should be considered when estimating Cl aminoglikosida non-renal Cl = 0.5 mL/menit/70 kg) • Non-renal Cl generally ignored in most patient. and temperature • Amikacin much less likely to interact with these penicillins • Cl Tobramycin.0021 L/kg/jam (= 2. ticarcillin.13/12/2014 Klirens (Cl) • Cl untuk morbidly obese (BB = 2*IBW) – BB = IBW + 0. the concentration of the penicillin compound.0043 L/kg/jam (5 mL/menit/70 kg) represents the residual renal klirens as well as non-renal klirens Klirens (Cl) • Carbenicillin. the penicillin compound. bila Vd 0. t1/2 = 6 jam • Initial aminoglikosida dose and dosing interval should be selected with care 8 . 70 kg. SCr 1. Vd sama.8 mg/dL Cl aminoglikosida = 100 mL/menit.13/12/2014 WAKTU PARO ELIMINASI (t1/2) 0. 25 tahun dengan SCr 0. 75 tahun.25 L/kg t1/2 = 2 jam – Pria.693𝑉 𝐷 • 𝑡1/2 = 𝐶𝑙 • Since renal function varies considerably among individuals.4 mg/dL Cl aminoglikosida = 35 mL/menit. t1/2 also variable • Contoh : – Pria. majority patient approching steady state by this time. Cp max about one hour after IM injection Cp max should be obtained in this time 9 . because aminoglikosida have a relatively short half-life and small but significant distribustion phase • Peak Cp be obtained one hour after the DM initiated. • When aminoglikosida administered IM. 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 : 𝐶𝑝 𝐶𝑝0 = −𝑘𝑡 𝑒 • 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. time aborption less predictable.13/12/2014 TIME TO SAMPLE • Correct timing of the sample collection important. 13/12/2014 PERSAMAAN • When duration infusion or absorption less than one-sixth of half-live (<1/6*t1/2) bolus dose model can be used : • Cp1 = 𝑆 𝐹 𝐷𝐿 𝑉𝑑 (𝑒 −𝑘𝑡1 ) PERSAMAAN • If duration drug input greater than one-half of half-live (>1/2*t1/2) the short infusion model used : • Cp2 = 𝑆 𝐹 𝐶𝑙 𝐷 𝑡𝑖𝑛 (1 − 𝑒 −𝑘𝑡𝑖𝑛 )(𝑒 −𝑘𝑡2 ) 10 . because have very short aminoglikosida half-live PERSAMAAN • If bolus dose model applied. used to predict the peak levels steady state : • 𝐶𝑝𝑠𝑠1 = 𝑆 𝐹 𝐷 𝑉𝑑 1−𝑒 −𝑘𝜏 (𝑒 −𝑘𝑡1 ) – t1= time interval between start infusion and time at “peak concentration” sample – 𝜏 = interval between dose 11 . use infusion model is more appropriate.13/12/2014 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). 13/12/2014 PERSAMAAN • Trough concentration (Cpss min) at steady state : 𝑆 𝐹 𝐷 𝑉𝑑 1−𝑒 −𝑘𝜏 • Cpss min = (𝑒 −𝑘 ) – 𝜏 = interval between dose PERSAMAAN • If infusion model used : • 𝐶𝑝𝑡𝑖𝑛 = 𝑆 𝐹 𝐶𝑙 𝐷 𝑡𝑖𝑛 (1 − 𝑒 −𝑘𝑡𝑖𝑛 ) – tin= duration infusion 12 . 13/12/2014 PERSAMAAN • Intermittent infusion steady state model : 𝑆 𝐹 • Cpss2 = 𝐶𝑙 𝐷 𝑡𝑖𝑛 1−𝑒 −𝑘𝑡𝑖𝑛 1−𝑒 −𝑘𝜏 𝑒 −𝑘𝑡2 – = 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 = 𝐷 𝑆 𝐹 𝑡 𝑖𝑛 𝐶𝑙 1−𝑒 −𝑘𝑡𝑖𝑛 1−𝑒 −𝑘𝜏 𝑒 −𝑘(𝜏−𝑡𝑖𝑛 ) – = dosing interval. – t2 = time interval between the end infusion and time at concentration measured = -tin 13 . 13/12/2014 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 = (𝐶𝑝𝑠𝑠2 )(1−𝑒 −𝑘𝜏 ) 𝑆 𝐹 𝑡𝑖𝑛 𝐶𝑙 (1−𝑒 −𝑘𝑡𝑖𝑛 )(𝑒 −𝑘𝑡2 ) • 𝜏 2*t1/2 atau lebih 14 . 13/12/2014 PERSAMAAN • To calculate DM untuk model iv bolus: • DM = (𝐶𝑝𝑠𝑠1 )(𝑉𝑑)(1−𝑒 −𝑘𝜏 ) (𝑆)(𝐹)(𝑒 −𝑘𝑡1 ) • 𝜏 2*t1/2 atau lebih PERSAMAAN • To calculate Cl bila ada TDM at steady state : • Cl = 𝐷 𝑆 𝐹 𝑡 𝑖𝑛 𝐶𝑝𝑠𝑠2 1−𝑒 −𝑘𝑡𝑖𝑛 1−𝑒 −𝑘𝜏 (𝑒 −𝑘𝑡2 ) 15 . 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. hitunglah konsentrasi tunak plasma maksimum dan minimum gentamisin 16 [email protected] mg/dL. no mhs. kelompok berapa dan FKK berapa • Analisis kasus-kasus berikut. Diberikan gentamicin dengan dosis awal 100 mg secara infus iv selama 30 menit. Hitunglah konsentrasi plasma gentamicin 1 jam setelah infus iv dimulai.. wanita dengan serum kreatinin 0. 30 tahun.13/12/2014 TUGAS KELOMPOK • Kirimkan email ke arief. • Bila gentamisin diberikan tiap 8 jam.com untuk minta materi kuliah dan tugas kelompok dengan menyebut nama. 70 kg. 38 tahun dengan serum kreatinin 1. konsentrasi tunak 12 jam setelah pemberian. Tobramycin diberikan infus iv selama 0. 50 kg.13/12/2014 Kasus 2 • L. Diberikan tobramycin 5 mg/kg sekali sehari secara infus iv selama 30 menit. diberikan infus iv tobramycin 100 mg selama 0. 70 kg. wanita dengan serum kreatinin 1 mg/dL diberikan tobramycin. Kasus 3 • Y. Konsentrasi maksimum plasma satu jam setelah infus dimulai 8 mg/L..8 mg/dL.K. dan konsentrasi minimalnya sesaat sebelum dosis berikutnya diberikan 3 mg/L. dan konsentrasi tunak minimalnya. 3 kali sehari untuk beberapa hari. Estimasikan harga konstanta kecepatan eliminasi. Agar dapat menghasilkan konsentrasi maksimum tunak 7 mg/L dan minimal tunaknya <2 mg/L 17 . 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. klirens.5 jam.K.. hitunglah konsentrasi tunak maksimum (satu jam setelah infus dimulai).B. dan volume distribusi tobramycin pada pasien tersebut • Rekomendasikan regimen dosis untuk pasien Y. 40 tahun. • Bila L.5 jam.B. . pria dibawa ke UGD. Kasus 5 • D. 18 .13/12/2014 Kasus 4 • D. Pasien memiliki tinggi badan 165 cm dan saat masuk UGM BB 85 kg.H.H. umur 38 tahun.. Menerima gentamicin sebagai terapi empiris paska operasi abdominal. riwayat gagal ginjal diberikan gentamicin dan carbenicillin. D. Rekomendasikan regimen dosis gentamisin agar dapat menghasilkan konsentrasi tunak maksimum 5-7 mg/L dan minimum <2 mg/L. Rekomendasikan regimen dosis gentamicin untuk pasien tersebut agar dapat menghasilkan konsentrasi tunak maksimal 8 mg/L dan minimal <2 mg/L. BB nya 105 kg dan serum kreatininnya 2 mg/dL. Saat ini.L. 70 kg. Pasien akan menjalani operasi abdominal dan setelah operasi mengalami hipotensi dan diberikan cairan infus dengan volum besar untuk menjaga tekanan darahnya. 40 tahun. yaitu pada jam 1:00. Hitunglah konsentrasi tunak maksimal tobramycin pada jam 10:00 (satu jam setelah infus dimulai). 9:00.C. 19 .13/12/2014 Kasus 6 • T. Diberikan tobramycin 120 mg secara infus iv selama 30 menit tiap 8 jam. dan 17:00.9 mg/L. Konsentrasi tunak tobramycin diukur pada jam 8:30 dan 11:30 dihasilkan kadarnya berturut-turut 0.9 mg/L dan 3.