Rozaimah Zain-HamidDepartment of Pharmacology and TherapeuticFaculty of Medicine, Universitas Sumatera Utara, Indonesia

CLINICAL PHARMACOKINETICS PRINCIPLERZH - Faculty of Medicine USU.

Clinical pharmacokinetics principle Determine the dose that most closely achieve desired beneficial effect with minimal adverse effectsTherapeutic drug concentration in plasma and tissue (target organ)RZH - Faculty of Medicine USU.

The plasma drug conc. Drugs effectThe various pathologic & physiologic features of particular patientRZH - Faculty of Medicine - USUDifferent response from average individual responding to a drug

Drug conc. (mg/l)Time (hour)102030401234m.s.cTherapeutic levelLow therapyDrug toxicityTime-drug conc. relationshipm.e.cRZH - Faculty of Medicine - USU

Factors that modify drug plasma concentration for a given doseDrug formulationDrug interactionEnvironmental factorsGenetic variationRenal and hepatic functionRZH - Faculty of Medicine USU.

PHARMACOKINETICS MODEL IN HUMANRZH - Faculty of Medicine USU.

There is no out movement of the drug. The graph shows only steep rise to maximum followed by plateau2. A route of elimination is present. The graph shows a slow decay after a sharp rise to maximumRZH - Faculty of Medicine USU.Pharmacokinetics model in human

3. Drug placed in the first compartment (blood) equilibrates rapidly with the second compartment (extravascular)4. The more realistic combination of elimination mechanism and extravascular equilibrationRZH - Faculty of Medicine USU.Pharmacokinetics model in human

LINEAR & NONLINEAR KINETICSRZH - Faculty of Medicine USU.

Linear kineticsFirst-order kineticsThe rate of drug elimination is directly proportionate to drug concentrationRZH - Faculty of Medicine USU.

Non-linear kineticsZero-order kineticsThe rate of drug elimination independent to drug conc.RZH - Faculty of Medicine USU.

Bila langkah pertama tak pernah ditapakkan, maka tidak pernah ada langkah berikutnyaRZH - Faculty of Medicine USU.

CLINICAL PHARMACOKINETICS PARAMETERSRZH - Faculty of Medicine - USU

RZH - Faculty of Medicine USU.1. Bioavailability (AUC)BioequivalencyBioinequivalencyDifference of bioavail. (10-50 %)Therapeutical equivalence* Diff. of patients characteristic () * Drugs interaction ()

RZH - Faculty of Medicine USU.Pharmacokinetic parameters Cmax (peak)Half lifeTime Cmin (trough)Drugs-plasma conc.(g/ml)AUC 24105

RZH - Faculty of Medicine - USU2. Volume of distribution (Vd)The measure of the apparent space in the body available to contain the drug

Volume of distribution (Vd) Relates the amount of drug in the body to the concentration of drug (C)amount of drug in bodyVd = CRZH - Faculty of Medicine USU.

RZH - Faculty of Medicine USU.Clinical application calculating loading dose required desired plasma concentration Volume of distribution (Vd)Loading dose = distr. vol desired conc.

RZH - Faculty of Medicine - USU3. Half life (t) Change of the drug conc. in the body by one-half of the previous concentrationthe time

RZH - Faculty of Medicine USU.Drug conc. (mg/l)51020642HoursVisualisation of half-life2.5t t t First order elimination of a drug (t : 2 hours)The plasma conc. falls by half each half-life

determining time required to reach a steady-state plasma level upon multiple dosing (full clinical effect of drug) corresponds to 3 to 5 half-life Clinical application of half life (t) RZH - Faculty of Medicine USU.

Clinical application of half life (t) * Designing drug dosage regimen* Determining time to reach steady state drug level which show clinical effect*Determining time to reach the drug level which have no clinical effect anymoreRZH - Faculty of Medicine USU.

Plasma theop.conc. (mg/l)Time (hours)10203040122436m.s.cTime-drug conc. relationshipm.e.c0Concentration time curve of theophylline (immediate release)Dose: 100 mg / 4hours (600 mg/day)RZH - Faculty of Medicine USU.

RZH - Faculty of Medicine USU.Plasma theop.conc. (mg/l)Time (hours)10203040122436m.s.cTime-drug conc. relationshipm.e.c0Concentration time curve of theophylline Dose: 300 mg /12 hours (600 mg/day) immediate release slow release

4. Clearance of the drug (CL) The measure of the ability of the body to eliminate drugRZH - Faculty of Medicine USU.

Clearance of the drug (CL) The ratio of the rate of elimination by all routes to the conc. of drug in a biologic fluidRZH - Faculty of Medicine USU.Rate of eliminationCL = C

RZH - Faculty of Medicine USU. determining the maintenance dose required a desired steady-state plasma conc. Clearance of the drug (CL) Maintenance dose = clearance desired conc.Clinical application

RZH - Faculty of Medicine USU. Maintenance infusion only Loading dose exactly right Loading dose over estimate Loading dose under estimate Loading dose followed by infusionDrug conc. (mg/l)10203040302010HoursUse of loading dose (infusion / i.v)

Arigato GozaimasuRZH - Faculty of Medicine USU.