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TUJUAN INSTRUKTIONAL UMUM: Mampu menerapkan prinsip-prisip biofarmasetika dan farmakikinetika dalam praktek kefarmasian ( misal Therapeutic Drug Monitoring atau TDM di rumah sakit ) SILABUS: 1. Pendahuluan 2. Peranan biofarmasetika dan farmakokinetika pada penggunaan klinis faktor fisiologi dan patologi yg mempengaruhi parameter biofarmasetika dan farmakokinetika 3. Bioavailabilitas dan bioekivalensi 4. Rentang terapetik dan penyusunan regimen dosis secara Farmakokinetik 5. Berbagai cara penyesuaian regimen dosisUntuk berbagai kondisi klinik ( gagal ginjal, gangguan hepar,Penyakit kronis, hemodialisa dsb ) dan monitoring kadar obat 6. Studi kasus untuk obat-obat khusus
TEAM PENYAJI
1. DR. Edy Suwarso S.U. (koordinator) 2. Dra. Azizah Nasution M.Sc. (anggota) 3. DR. Karsono 4. DR. M. T. Simanjuntak 5. Drs. Kasmirul Ramlan Sinaga M.S.
Goals : 1. To provide the student with an understanding of how the principles of biopharmaceutics and pharmacokinetics relate to clinical setting. 2. To provide the student with an understanding of the aplication of serum concentrations to monitoring drug therapy. Objectives : 1. Define: biopharmaceutics, pharmacokinetics, pharmacodynamics and applied pharmacokinetics. 2. Discuss how inter-patient variability in pharmacokinetics and pharmacodynamics has led to serum concentration monitoring as an intermediate therapeutic endpoint. 3. Discuss the factors that can alter absorption, distribution, metabolism and excretion. 4. Discuss the correlation of serum concentration, concentration at the site of actionand therapeutic response. 5. Define therapeutic range and discuss its limitations. 6. Discuss the applied pharmacokinetic approach to
BIOPHARMACEUTICS : is define as the study of the relationship between some of the physical and chemical properties of the drug and its dosage form and the bological effect following its administration in man and animals. PHARMACOKINETICS: What the body does to the drug! is the study of absorption, distribution, metabolism, and excretion of drugs (WHO). CLINICAL PHARMACOKINETICS or APPLIED PHARMACOKINETICS is the process of using drug concentrations, pharmacokinetic principles, and pharmacodynamic criteria to optimize drug therapy in individual patients. PHARMACODINAMICS: What the drug does to the body! The study of biochemical and physiological effects of the drug and their mechanism of action. THERAPEUTIC DRUG MONITORING and CLINICAL PHARMACOKINETICS are used as near synonyms for this process of using drug concentrations as a guide in therapy.
Drugs which are monitored by serum concentration measurement usually have the following properties : 1. Serum concentrations quantitatively correlate with the probability or intensity of response and toxicity. 2. Low therapeutic index, a narrow range of concentration which provide and optimal outcome. 3. Variable pharmacokinetics such that the relationship bet ween dose and response is difficult to predict.
Pharmacokinetics relates the dose to the serum concentration. Pharmacodynamics relates the serum concentration to the therapeutic response
Pharmacokinetic principles
Pharmacokinetic principles of calculating dosage regimens can be applied to most drugs. Pharmacokinetic parameters ( V, Cl, t1/2,fu) vary from drug to drug, and from patient to patient for a single drug. This variability should be considered when calculating dosage regimens. By assessing the serum concentration resulting from a known dosing regimen, the parameter for a given drug in an individual patient may be calculated and used to aid further dosing adjustments in that patient.
2.
Sites of metabolism
Liver
OXIDATION
Kidney
REDUCTION
HYDROLYSIS
CONJUGATION
Lung
Pharmacodynamic Principles
Pharmacodynamics is the relation of drug concentrations in the serum ( or more exactly at the sitr of action ) with pharmacologic response. According to receptor theory, a pharmacologic effect is achieved by the interaction of free (unbound) drug and a reseptor at the site of action. As the free drug concentration at the site of action is frequently difficult to measure , alternatives must be sought. Free drug concentration site of action In equilibrium with Free drug concentration plasma or serum In equilibrium with Total drug concentration plasma or serum Based upon the relationship, it would reasonable to assume that: - The drug concentration in the serum reflects the concentration at the site of action. - The total serum concentration of a drug could be correlated with the pharmacologic or toxic effects.
This is the basis of pharmacodynamics and the application of serum concentration monitoring and pharmacokinetics as a guide in optimizing drug therapy.
Several factors introduce variability into concentration effect relationship : 1. 2. 3. 4. 5. 6. 7. Physiologic or pharmacologic agonists or antagonists. Genetic factors Severity of disease Distribution to the site of action Protein binding free concentration Tolerance or tachyphylaxis Active or antagonistic metabolites.
2. 3. 4. 5. 6. 7.
PELAKSANAAN TDM
1. Physician ( dokter ) : Mendiagnosa penyakit Memilih obat,dosis dan interval Memonitor respon klinik 2. Clinical Pharmacist ( apoteker ) : Mengkordinasikan wkt pengambil an sampel yg sesuai Interpretasi hasil SDC Berkordinasi dgn dokter utk menentukan dosis yg tepat Membantu monitoring respon klinik
3. Nurse ( perawat ) : Memberikan dan mendokumen tasikan obat yg diberikan. Memonitor respon klinik.
4.
Laboratory personnel : Mencatat wkt pengambilan specimen pemberian dosis dan rute Memberikan hasil SDC. Membatu interpretasi hasil SDC.
Goal: use serum concentrations as a aid in optimizing drug therapy in individual patients to maximize the probability of therapeutic effect and to minimize the probability of toxicity.
Therapeutic Range
The therapeutic range is most often thought of as the window or range of serum concentrations that are associated with a therapeutic benefit without toxicity. Some common misconceptions of the therape utic range are : 1. Concentration in this range should always produce the desire response. 2. Toxicity is not encountered at concentrations within this range. The therapeutic range is not an absolute range of guaranteed response without toxicity. Instead, it should be thought of as a range of probability: 1. High probability of desired/therapeutic response. 2. Low probability of unacceptable toxicity.
Prospective (expectation), well controlled trials? Patients studied: age, weight/degree of obesity, type and severity of illness. Concurrent diseases Concurrent drug therapy accuracy and precision of effect measurement Accuracy and precision of drug concentration measurement
Variable between and within patients exist for both : 1. Pharmacokinetics of a drug (dose-concentration relationship) 2. Pharmacodynamics of a drug (concentration-effect relationship)
5.2.2. Determine the maximum dosing interval possible based on the available MEC and Cmax
C . ln max C min
5.2.4. Multiply the value of chosen by the rate of dosing determined in step 5.2.1 6. Monitor patients response to dosing regimen. 7. Obtain serum concentration (s) at the appropriate time. 8. Determine if dosing adjustments are necessary based upon therapeutic response or evidence of toxicity 9. Use serum concentration (s) to estimate kinetic parameters for the individual patient and calculate a new dosing regimen based upon this new information. 10. Go back to step 6.
2.
Rute i.m
3.
Rute per oral: Kecepatan per oral bervariasi, tergantung kpd banyak faktor spt tlh diuraikan terlebih dahulu.Biasanya pengambilan sam pel dilakukan pada tmax obat ybs. Rute infus : Pengambilan sampel biasanya dilakukan bbrp saat sebelum atau sesudah dicapai Css ( Css dicapai dlm waktu 3,3 t1/2 ).
4.
PENYESUAIAN DOSIS PADA PASIEN GAGAL GINJAL Ginjal merupakan organ utama pengeliminasi berbagai senyawa dari dalam tubuh termasuk obat dan metabolitnya. Apabila terjadi gangguan ginjal, maka eliminasi obat juga akan terganggu dan akan mengakibatkan akumulasi di dalam tubuh selanjutnya dapat mengakibatkan efek toksik. Oleh karena itu, agar diperoleh efek terapi yang optimal, maka dosis obat perlu disesuaikan
Input obat Per oral : F x D/ xCss IV ( dosis berganda ) : D/ xCss Infus : LD = V . Css R ( Rate of Infusion )
TUBUH
Eliminasi
= = k . V. Css =
Cl
Cl
Cl x Css
Cl (ri) = clearance utk pasien dgn gagal ginjal Cl (nl) = clearance utk pasien ginjal normal
TAHAPAN (LANJUTAN) Hitung dosis dengan memasukkan nilai Cl (ri), dan Css yg dipilih ke dalam persamaan diatas (per oral, iv ataupun infus ).
Contoh kasus
Seorang pasien ( AG ), laki-laki, 46 thn menderita GGK . Nilai Creatinine 0,5 mg/dl, nilai creatinine normal adalah 0,7 1,4 mg/dl. Mula-mula pasien diberi Seftriaxone inj ( vial 1 gram/ 12 jam ) selama 4 hari, kemudian diganti dengan Siprofloksasin ( 2 x 250 mg ) selama 2 hari. Data parameter farmakokinetik Siprofoksasin adalah sbb : t = 4 jam ; V = 2L/kgBB ; F = 0,8 ; Range Terapi = 3,4 -4,3 ng/ml, fe = 40 65 %, BB = 55 kg. Hitung dosis Siprofoksasin berdasarkan creatinine clearance pasien. Jawab : 0,5m g / dl KF =CrCl ( ri ) / CrCl ( nl ) = = 0.48
1,05m g / dl
Tentukan fraksi obat tak berubah yang dieksresikan oleh ginjal ( fe ) untuk pasien dengan ginjal normal fe = Cl R / Cl = kR / k = diperoleh dari literature 40 -65 % 50 %
= 1 fe . ( 1 KF ) Cl (ri) = Cl(nl) { 1-fe. ( 1 KF ) } = 18,7 L/jam { 1-0,5 ( 1 0,48 ) } = 18,7 L/jam . 0,74 = 13,8 L/jam F x D/ = Cl xCss 0,8 . D/ = 13,8 L/jam . 4 ng/ml 0,8 . D/= 13800 ml/jam.4 ng/ml
D/ = 69000ng/jam = 69mcg/jam
LANJUTAN Pada kasus ini interval pemberian terlalu panjang yi 12jam ,sedangkan t1/2nya singkat dan range terapi sempit secara teori, konsentrasi obat di dalam plasma akan cepat turun. Oleh karena Itu, perlu ditentukan max dengan rumus sbb : max = 1.44 t1/2 . ln 1,44 . 4 jam .ln =1.44 . 4 jam . (1,5 1,2) = 1,7 = 2 jam Pilih interval 6, 8, 12 atau 24 jam, maka yang paling mendekati adalah 6 jam. Dosis = 6 jam . 69 mcg /jam = 414 mcg Bila interval pemberian = 12 jam, maka : Dosis = 12 jam . 69 mcg/jam = 828 mcg
C max C min =
4,3 3,4