Designing a Dosage Regimen Pertemuan II Farmakokinetika Klinik Tunggul AP, M.Sc., Apt.

Dosis yang diberikan (Resep) Compounding and Dispensing Kepatuhan Penderita Dosis yang diminum Faktor-faktor farmakokinetika Absorpsi (jumlah dan kecepatan) Distribusi (ukuran dan komposisi tubuh, distribusi dalam cairan2 tubuh, ikatan protein Eliminasi Kondisi fisiologik Kondisi patologik Faktor genetik Interaksi obat Toleransi Kadar Di Tempat Kerja Faktor-faktor farmakodinamik Interaksi obat-reseptor Keadaan fungsional jaringan Mekanisme homeostatik Sensitivitas reseptor/jaringan Intensitas Efek Farmakologik (Respon Penderita)

PEMILIHAN OBAT INDIKASI TERAPETIK SAMA –PROFIL FARMAKOKINETIKA BERBEDA DIDASARKAN PADA DIGNOSIS YANG TEPAT FARMAKODINAMIK DAN KADAR TERAPETIK F.KINETIKA OBAT KONDISI PATO-FISIOLOGIS RIWAYAT PENGOBATAN SEBELUMNYA TERAPI TUNGGAL / GANDA ALERGI / KEPEKAAN DAFTAR OBAT ESENSIAL HARGA KENYAMANAN & KEPATUHAN

Prinsip pendosisan (dosage regimen) Berapa banyak, berapa sering, berapa lama ? Initial dose, maintainance dose, discontinuing the dose

Activity-Toxicity Pharmacokinetics Dosage Regimen Clinical Factors Therapeutic window Side effects Toxicity Concentration-response relationship Pharmacokinetics Absorption Distribution Metabolism Excretion Dosage Regimen Clinical Factors Other Factors Route of administration, Dosage form, Tolerance-Pharmacogenetics- Drug interactions , Cost Management of therapy Multiple drug therapy Convenience of regimen Compliance of patient State of patient Age, weight ,Condition being treated, Existence of other disease states

RANCANGAN ATURAN DOSIS ACTIVITY –TOXICITY RANCANGAN ATURAN DOSIS ACTIVITY –TOXICITY TERAPEUTIC WINDOW SIDE EFFECT TOXICITY CONCENTRATIONS-RESPONS RELATIONSHIPS

PHARMACOKINETICS ABSORPTION DISTRIBUTION METABOLISM EXCRETION

CLINICAL FACTORS STATE OF PATIENT : AGE, WEIGHT,GENDER, NUTRITIONAL, CONDITION BEING TREATED, RENAL DYSFUNCTION, LIVER DEASESE, CONGESTIVE HEART FAILURE EXISTENCE OF OTHER DESEASE STATES MANAJEMEN OF THERAPY : MULTIPLE DRUG THERAPY CONVENIENCE OF THERAPY COMPLIANCE OF PATIENT

OTHER FACTORS - ROUTE OF ADMINISTRARION - DOSAGE FORM - TOLERANCE - PHARMACOGENETICS - DRUG INTERACTIONS : ENVIROMENTAL FACTORS (SMOKING) - CELL TARGET (RECEPTOR) SENSITIVITY - COST

monitoring A diagnosis is made A drug is selected Dosage schedule is designed to reach a target plasma concentration Drug is administered If dosage adjustment necessary Patient assessments are performed Drug concentrations are determined A pharmacokinetic model is applied and clinical judgement is used Figure Process for reaching dosage decisions with therapeutic drug monitoring

PENILAIAN RESPON PENDERITA RESPON POSITIF : TERUS RESPON KURANG : -EVALUASI DOSIS & INTERVAL ; INTERAKSI -EVALUASI FARMAKODINAMIK -KEPATUHAN RESPON NEGATIF : STOP

# of People Value of PK Parameter Population versus Individual Values for PK Parameters Rarely Available PK Values Widely Available PK Values # of People Value of PK Parameter Population values represent average values rather than the value for YOUR patient. Individual values represent the values in YOUR patient, but they have to be determined in YOUR patient.

If available, of course use individual values for PK parameters. Population versus Individual Values for PK Parameters If available, of course use individual values for PK parameters. You will nearly always have to settle for population values for PK parameters.

Designing a Dosage Regimen Decide whether LD is required and, if so, calculate LD.

Can you afford to wait 4t1/2s to obtain [D]PSS? Yes No Do not give LD. Calculate LD.

Capacity-Limited Metabolism (Also called “Zero Order Kinetics”) An infrequent, but important phenomenon Clearance is not constant with respect to [D]P because metabolizing enzymes are saturated at “therapeutic concentrations” Rate of drug elimination is fixed and cannot use clearance to calculate dosage regimen For such drugs, daily dose should not exceed fixed rate of elimination

A dosage regimen may need to be adjusted if plasma clearance changes, for instance because of disease.

Adjusting Dosage Regimens in Patients with Renal Disease If drug is eliminated mostly by liver, no adjustment required. If drug is eliminated mostly by kidney, either: Re-evaluate need for drug and discontinue if possible Reduce dose Increase dosing interval Switch to drug eliminated mostly by liver Contoh: Vancomycin population pharmacokinetic Dosage nomogram of vancomycin

Adjusting Dosage Regimens in Patients with Liver Disease If drug is eliminated mostly by kidney, no adjustment required. If drug is eliminated mostly by liver, either: Re-evaluate need for drug and discontinue if possible Reduce dose Increase dosing interval Switch to drug eliminated mostly by kidney

HOW DO I DESIGN AND ADJUST A DOSAGE REGIMEN? Now you know!!

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