BIOPHARMACEUTICS AND CLINICAL PHARMACOKINETICS

TUJUAN INSTRUKTIONAL UMUM:Mampu menerapkan prinsip-prisip biofarmasetika dan farmakikinetika dalam praktek kefarmasian ( misal Therapeutic Drug Monitoring atau TDM di rumah sakit )

SILABUS:1. Pendahuluan2. 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

Farmakokinetik5. 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 :Goals :1.1. To provide the student with an understanding of how To provide the student with an understanding of how

the principles of biopharmaceutics and the principles of biopharmaceutics and pharmacokinetics relate to clinical setting.pharmacokinetics relate to clinical setting.

2.2. To provide the student with an understanding of the To provide the student with an understanding of the aplication of serum concentrations to monitoring drug aplication of serum concentrations to monitoring drug therapy.therapy.

Objectives :Objectives :1.1. Define: biopharmaceutics, pharmacokinetics, Define: biopharmaceutics, pharmacokinetics,

pharmacodynamics and applied pharmacokinetics.pharmacodynamics and applied pharmacokinetics.2.2. Discuss how inter-patient variability in Discuss how inter-patient variability in

pharmacokinetics and pharmacodynamics has led to pharmacokinetics and pharmacodynamics has led to serum concentration monitoring as an intermediate serum concentration monitoring as an intermediate therapeutic endpoint.therapeutic endpoint.

3.3. Discuss the factors that can alter absorption, Discuss the factors that can alter absorption, distribution, metabolism and excretion.distribution, metabolism and excretion.

4.4. Discuss the correlation of serum concentration, Discuss the correlation of serum concentration, concentration at the site of actionand therapeutic concentration at the site of actionand therapeutic response.response.

5.5. Define “ therapeutic range “ and discuss its Define “ therapeutic range “ and discuss its limitations.limitations.

6.6. Discuss the applied pharmacokinetic approach to Discuss the applied pharmacokinetic approach to optimizing drug dosing and therapy.optimizing drug dosing and therapy.

7.7. Discuss the factors that should be considered when Discuss the factors that should be considered when evaluating serum concentrations of drug.evaluating serum concentrations of drug.

• 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

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 principlesPharmacokinetic principles

• Pharmacokinetic principles of calculating Pharmacokinetic principles of calculating dosage regimens can be applied to most dosage regimens can be applied to most drugs.drugs.

• Pharmacokinetic parameters ( V, Cl, tPharmacokinetic parameters ( V, Cl, t1/21/2,fu) ,fu) vary from drug to drug, and from patient to vary from drug to drug, and from patient to patient for a single drug. This variability patient for a single drug. This variability should be considered when calculating should be considered when calculating dosage regimens.dosage regimens.

• By assessing the serum concentration By assessing the serum concentration resulting from a known dosing regimen, the resulting from a known dosing regimen, the parameter for a given drug in an individual parameter for a given drug in an individual patient may be calculated and used to aid patient may be calculated and used to aid further dosing adjustments in that patient.further dosing adjustments in that patient.

• Pharmacokinetic principles of calculating Pharmacokinetic principles of calculating dosage regimens can be applied to most dosage regimens can be applied to most drugs.drugs.

• Pharmacokinetic parameters ( V, Cl, tPharmacokinetic parameters ( V, Cl, t1/21/2,fu) ,fu) vary from drug to drug, and from patient to vary from drug to drug, and from patient to patient for a single drug. This variability patient for a single drug. This variability should be considered when calculating should be considered when calculating dosage regimens.dosage regimens.

• By assessing the serum concentration By assessing the serum concentration resulting from a known dosing regimen, the resulting from a known dosing regimen, the parameter for a given drug in an individual parameter for a given drug in an individual patient may be calculated and used to aid patient may be calculated and used to aid further dosing adjustments in that patient.further dosing adjustments in that patient.

FACTORS THAT AFFECT ABSORPTION FACTORS THAT AFFECT ABSORPTION

• Route : PO, SL, BUCCAL, RECTAL, IV, IM, INHAL ETC.

• BIOLOGIC :Blood flowGI pHgastric emptyingfoodmalabsorptionagestomach diseaseintestinal disease

• Route : PO, SL, BUCCAL, RECTAL, IV, IM, INHAL ETC.

• BIOLOGIC :Blood flowGI pHgastric emptyingfoodmalabsorptionagestomach diseaseintestinal disease

• Chemical :drug pKalipid solubilitysalt/crystal formsurface area/sizepH stability.

• Dosage form :solutionsuspensioncapsultabletDISINTEGRATIONDISSOLUTION

• Chemical :drug pKalipid solubilitysalt/crystal formsurface area/sizepH stability.

• Dosage form :solutionsuspensioncapsultabletDISINTEGRATIONDISSOLUTION

FACTORS THAT AFFECT DISTRIBUTIONFACTORS THAT AFFECT DISTRIBUTION1. Perfusion limited : tissue presents no barrier to

distribution (small, very lipid soluble drugs).- blood flow determines rate of distribution -relative solubility in blood and tissue determines extent.- CHF and other states of poor perfusion.

2. Diffusion limited: tissue does pose a barrier to distribution (polar drugs).- lipid solubility- ionization- molecular weight.

1. Perfusion limited : tissue presents no barrier to distribution (small, very lipid soluble drugs).- blood flow determines rate of distribution -relative solubility in blood and tissue determines extent.- CHF and other states of poor perfusion.

2. Diffusion limited: tissue does pose a barrier to distribution (polar drugs).- lipid solubility- ionization- molecular weight.

Factors that affect distribution (continued)

3. Protein binding to plasma and tissue

proteins.

– AAG binds basic drugs

– albumin binds acidic drugs

–The more highly bound to plasma proteins , the smal

ler the V and the more quickly distribution is achieved. –The free drug concentration is the active amount

– Hypoalbuminemia, surgery, trauma, malnutrition, MI.

Factors that affect MetabolismFactors that affect Metabolism

ROUTES OF METABOLISM

OXIDATION

REDUCTION

HYDROLYSIS

CONJUGATION

Sites of metabolism

Liver

Kidney

GI Tract membranes

Skin

Blood

Lung

Factors that affect metabolism

• Enzyme induction: metabolism can be stimulated by some drugs or chemicals (i.e. phenytoin, phenobarbital, rifampin, cigarette smoke, etc.).

• Enzyme inhibition: some drugs inhibit the function of metabolic enzymes (i.e. cimetidine).

• Metabolites: active or inactive metabolites formed may interfere with the binding or metabolism of parent drug.

• Saturation: may deliver more drug than enzyme can metabolize.

• Other factors:liver blood flowenzyme function (age, amount)liver disease (hepatitis, cirrhosis)concurrent drug/chemicals (induction or inhibition)

• Enzyme induction: metabolism can be stimulated by some drugs or chemicals (i.e. phenytoin, phenobarbital, rifampin, cigarette smoke, etc.).

• Enzyme inhibition: some drugs inhibit the function of metabolic enzymes (i.e. cimetidine).

• Metabolites: active or inactive metabolites formed may interfere with the binding or metabolism of parent drug.

• Saturation: may deliver more drug than enzyme can metabolize.

• Other factors:liver blood flowenzyme function (age, amount)liver disease (hepatitis, cirrhosis)concurrent drug/chemicals (induction or inhibition)

Enzyme P450 Inducers

1. Barbiturates : Phenobarbital etc

2. Cigarette smoke ( nicotin )

3. Phenylbutazone

4. Phenytoin

5. Rifampin ( probably )

6. Glucagon

7. Isoproterenol

Enzyme P450 Inhibitors

1. Erythromycin

2. Oral contraceptives

3. Cimetidine

4. Isoniazide

5. Propoxyphene

6. Triacetyloleanamycin

7. Norepinephrine

8. Propranolol

9. Metoprolol

Factors that affect ExcretionFactors that affect Excretion

• Biliary: drugs &/or metabolites may be excreted into the bile and eliminated through the intestinal tract.

sometimes they are reabsorbed into the body , (Enterohepatic recirculation).

• Renal: many drugs and metabolites are eliminated unchanged into the urine. Overall: The more polar the drug ionized drugs are elimi nated by the kidney. The goal of metabolism is to make a drug more polar so that it is eliminated by the kidney.

• Other factors: age renal function (filtration

rate) concurrent drug urine pH drug pKa urine flow rate

• Biliary: drugs &/or metabolites may be excreted into the bile and eliminated through the intestinal tract.

sometimes they are reabsorbed into the body , (Enterohepatic recirculation).

• Renal: many drugs and metabolites are eliminated unchanged into the urine. Overall: The more polar the drug ionized drugs are elimi nated by the kidney. The goal of metabolism is to make a drug more polar so that it is eliminated by the kidney.

• Other factors: age renal function (filtration

rate) concurrent drug urine pH drug pKa urine flow rate

Pharmacodynamic PrinciplesPharmacodynamic 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 actionFree drug concentration – site of actionIn equilibrium withIn equilibrium with

Free drug concentration – plasma or serumFree drug concentration – plasma or serumIn equilibrium withIn equilibrium with

Total drug concentration – plasma or serumTotal drug concentration – plasma or serumBased 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.

• 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 actionFree drug concentration – site of actionIn equilibrium withIn equilibrium with

Free drug concentration – plasma or serumFree drug concentration – plasma or serumIn equilibrium withIn equilibrium with

Total drug concentration – plasma or serumTotal drug concentration – plasma or serumBased 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. Physiologic or pharmacologic agonists or antagonists.

2. Genetic factors3. Severity of disease4. Distribution to the site of action5. Protein binding – free concentration6. Tolerance or tachyphylaxis7. Active or antagonistic metabolites.

THERAPEUTIC DRUG MONITORING ( TDM )

TDM telah menjadi suatu pelayanan yg essential untuk kondisi pasien krinis &

kritis di rumah sakit. Hal ini bukan hanya krn akibat pesatnya perkembangan

Pharmacology, Analytical chemistry dan Clinical medicine, ttp juga sbg akibat

munculnya obat yg memerlukan monitoring rutin agar dicapai efek terapi

Optimal.

Terapi Optimal yaitu kondisi dimana efek pengobatan maksimal,efek toksik dan efek samping diminimalkan.

TDM perlu dilaksanakan untuk obat dgn kriteria sbb :

1. Hubungan dosis dgn response sulit diperkirakan

2. Tidak mempunyai titik akhir klinis yg jelas

3. Range terapi jelas

4. Range terapi sempit

TDM melibatkan pengukuran serum drug concentration ( SDC ) dan clinical pharmacokinetics. Berbagai golongan obat mempunyai hubungan ( ko relasi ) yg baik dgn respons farmakologi.

Commonly Monitored Drugs

1. Antibiotics :AminoglycosidesImmunusuppressive agents ( cyclosporine )ChloramphenicolVancomycinOther antiinfective agents

2. Bronchdilator3. Analgesic, Antipyretic, Antiinflammatory Agents4. Antiepileptics : phenobarbital, phenytoin etc.5. Antineoplastics6. Cardiac Agents : antiarhytmics ( lidocain, propranolol etc.)

cardiac glycosides ( digitoxin, digoxin )7. Psychoactive agents

Tricyclic Antideppressants :amitriptyline, imipramine etcLithium

PELAKSANAAN TDM

1. Physician ( dokter ) :

Mendiagnosa penyakit

Memilih obat,dosis dan

interval

Memonitor respon klinik

2. Clinical Pharmacist ( apoteker ) :

Mengkordinasikan wkt pengambilan sampel yg sesuaiInterpretasi 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.

Serum Concentration Monitoring

• Prior to serum concentration monitoring, the appropriateness of dosage regimens was evaluated by monitoring the therapeutic or beneficial effects of the drug while observing the patient for any adverse o r toxic effects.

• Serum concentration monitoring has been used as an intermediate endpoint in therapy to aid in the attainment of therapeutic effects while avoiding toxicity.

• It is specially useful in the management of drugs with a narrow therapeutic index and variable pharmacokinetics.

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 RangeTherapeutic RangeThe 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 therapeutic 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.

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 therapeutic 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.

Variables to consider when evaluating studies reporting pharmacokinetic/concentration-response relationship

Variables to consider when evaluating studies reporting pharmacokinetic/concentration-response relationship

• 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)

Clinical Pharmacokinetic Approach to Drug Therapy

1. Asses the clinical state of the patient.2. Determine if any drug/disease states are present which may alter either

the pharmacokinetics or pharmacodynamics of the drug.3. Estimate the most appropriate kinetic parameters for the patient (V, Cl,

k, t1/2. fu) based upon clinical condition. 4. Determine route of administration.5. Choose average required serum concentration considering point 1.

5.1. IV BOLUS AND INFUS5.1.1. Calculate loading dose : LD = V x Css5.1.2. Calculate maintenance dose : MD = Cl x Css

5.2. IV and EXTRAVASCULAR MULTIPLE DOSES : 5.2.1. Determine the rate of dosing needed to achieve the average C chosen in step 5.

5.2.2. Determine the maximum dosing interval possible based on the available MEC and Cmax

max =1.44 t1/2 . lnז

5.2.3. Choose a ז of either 6, 8, 12 or 24 hours (especially if giving oral doses).

F

CavClD .

min

max

C

C

5.2.4. Multiply the value of ז chosen by the rate of dosing determined in step 5.2.1

6. Monitor patient‘s 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.

PENGAMBILAN SAMPEL DARAH

Waktu pengambilan sampel tergantung kepada rute pemberian dan farmakokinetik

obat.

1. Rute IV : konsentrasi maksimum cepat dicapai

pengambilan sampelbiasanya dilakaukan 20 s/d 30 menit setelah obat diberikan.

untuk antibiotika gol. Aminoglikosida sampel diambil 30- 60

minit setelah obat diberikan.

2. Rute i.m : Konsentrasi maksimum dicapai biasanya 30- 60 menit setelah

obat diinjeksikan.

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.

4. Rute infus : Pengambilan sampel biasanya dilakukan bbrp saat sebelum

atau sesudah dicapai Css ( Css dicapai dlm waktu 3,3 t1/2 ).

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

INDIKATOR FILTRASI GLOMERULUS • Inulin

merupakan senyawa eksogen ( suatu polysaccharide ), jadi kurang bermanfaat untuk penentuan rutin Glomerular Filtration Rate ( GFR ).

• Blood Urea Nitrogen ( BUN )

merupakan senyawa endogen dan mudah ditentukan, namun mempunyai beberapa kelemahan yaitu terjadi reabsorpsi secara signifikan sehingga tergantung kepada urine flow rate . Selain itu produksi urea oleh hati tidak konstan.

• Creatinine

merupakan senyawa endogen yang mudah ditentukan, namun juga mempunyai kelemahan karena nilai creatinine clearance yang sebenarnya adalah 10 % lebih besar dari GFR karena sekresi tubular dari creatinine. Walaupun demikian, hasil pengukuran creatinine clearance biasanya lebih tinggi sebesar 10 – 20 % karena “ noncreatinine chromogens “ikut terdeteksi. Akibatnya, nilai creatinine clearance yang diperoleh umumnya sudah dapat dijadikan sbg indicator GFR.

KONSEP DASAR PENGATURAN DOSIS OBAT

• Banyak obat yang mempunyai korelasi yang baik antara konsentrasi di dalam plasma dengan yang berikatan dengan reseptor, sehingga secara umum dapat diasumsikan bahwa konsentrasi obat di dalam plasma sebanding dengan yang berikatan dengan reseptor ( yang menghasilkan respon farmakologi ).

• Dengan demikian, pengaturan respon secara tidak langsung dapat dilakukan dengan mengatur konsentrasi obat di dalam plasma agar berada dalam range terapi ( tetapi perlu diingat bahwa range terapi tidak mutlak dapat menjamin respon tanpa toksisitas, tetapi dapat dianggap sebagai range probabilitas (probabilitas efek terapi tinggi dan efek toksik rendah ).

Input obat Eliminasi Per oral : F x D/ז = Cl xCss = k . V. Css IV ( dosis berganda ) : D/ז = Cl xCss Infus : LD = V . Css R ( Rate of Infusion ) = Cl x Css

TUBUH

TAHAPAN PELAKSANAAN PENGATURAN DOSIS Tentukan fungsi ginjal ( Kidney Function =KF ) dgn rumus

KF =CrCl ( ri ) / CrCl ( nl )CrCl ( ri ) = Creatinine clearance utk pasien dgn

gangguan ginjal CrCl ( nl ) = Creatinine clearance utk pasien ginjal normal

Tentukan fraksi obat tak berubah yang dieksresikan oleh ginjal ( fe ) untuk pasien dengan ginjal normal

fe = Cl R / Cl = kR / k Ini dpt dilihat dari literatureTentukan Clearance obat pada pasien gagal ginjal dengan menggunakan rumus berikut :

= 1 – fe . ( 1 – KF )

Cl (ri) = clearance utk pasien dgn gagal ginjal Cl (nl) = clearance utk pasien ginjal normal

)(

)(

nlCl

riCl

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 ½ = 4 jam ; V = 2L/kgBB ; F = 0,8 ; Range Terapi = 3,4 -4,3ng/ml, fe = 40 – 65 %, BB = 55 kg. Hitung dosis Siprofoksasin berdasarkan creatinine clearance pasien.Jawab :KF =CrCl ( ri ) / CrCl ( nl ) = = 0.48 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 %

dlmg

dlmg

/05,1

/5,0

LANJUTAN CONTOH KASUSTentukan Clearance obat pada pasien gagal ginjal dengan menggunakan rumus berikut :k = 0,693/ t ½ = 0,693/4 jam = 0,17 jam-1 Cl(nl) = k.V = 0,17 jam-1 . 2L/kg . 55kg = 18,7 L/jam

= 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/τ = Cl xCss 0,8 . D/τ = 13,8 L/jam . 4 ng/ml 0,8 . D/τ= 13800 ml/jam.4 ng/ml D/τ = 69000ng/jam = 69mcg/jam

)(

)(

nlCl

riCl

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 τmax dengan rumus sbb :

τmax = 1.44 t1/2 . ln = 1,44 . 4 jam .ln =1.44 . 4

jam . (1,5 – 1,2) = 1,7 = 2 jamPilih interval 6, 8, 12 atau 24 jam, maka yang paling mendekati adalah 6 jam.Dosis = 6 jam . 69 mcg /jam = 414 mcgBila interval pemberian = 12 jam, maka :

Dosis = 12 jam . 69 mcg/jam = 828 mcg

min

max

C

C4,3

3,4