1. Drug Administration Pharmacokinetic Phase (Time course of ADME processes) Absorption Distribution Pharmaceutical Phase Disintegration of the Dosage Form Drug and Drug Dissolution Active Site Metabolism Excretion Accumulation Pharmacodynamic Phase Pharmacological Effects Therapeutic EffectsToxic Effects

2. I.V. Bolus

3. Oral administration

5. Half-life Time for the concentration to decrease by half Clearance Volume of Distribution

6. SYSTEMIC EXPOSURE PARAMETERS Peak Drug Concentration (C max ) and AREA UNDER THE PLASMA CONCENTRATION TIME CURVE (AUC)

7. Multiple I.V. Dosing (Bolus) The AUC within a dosing interval at steady state is equal to the total AUC of a single dose.

9. Oral administration Multiple Dose

10. CONCEPT The absorption, distribution and elimination of a drug may be qualitatively similar in all individuals. However, for several reasons, the quantitative aspects may differ considerably. Each person must be considered individually and doses adjusted accordingly.

11. Daily Dose (mg/kg) Plasma Drug Concentration (mg/L) 051015 0 10 20 30 40 50 60 Variability in Pharmacokinetics

12. Co-variates affecting Drug Disposition Age Gender Genetic Make-Up Dietary Factors Environmental Factors Drug-Drug Interactions Disease State

13. PHARMACOKINETIC MODELING

14. Pharmacokinetic models are used to: Predict plasma, tissue and urine drug levels with any dosing regimen Calculate the optimum dosage regimen for each patient individually Estimate the possible accumulation of drugs and/or metabolites Correlate drug concentrations with pharmacologic or toxicologic activity Evaluate differences in the rate or extent of availability between formulations (bioequivalence) Describe how changes in physiology or disease affect the ADME of the drug Explain drug interactions

15. I. Physiologic Models Arterial blood Venous blood QHQH QMQM QSQS QRQR QKQK QLQL keke Urine kmkm IV injection

16. I. Physiologic Models Important factors – 1. Organ tissue size 2. Blood flow 3. Drug tissue-blood ratios Can be applied to several species (extrapolation of human data from animal data) Also known as blood flow/perfusion models

17. II. Compartmental Modeling

18. 1. Catenary Models 13 2 kaka k 12 k 21 k 23 k 32

19. 2. Mammillary Modeling Central P1 P2 P3 P4

20. One-Compartment Open Model D B 1 Cp 1 Vd I.V. bolus k 10 K 10 = overall elimination rate constant

21. I.V. Bolus

22. Two-compartment Open Model Cp 1 VC Dp Dt Ct Vt I.V. bolus k 12 k 21 tissue

23. Two-compartment model   b a C0C0

24. Plasma concentration (single dose) 1 -phase: distribution phase z -phase: elimination phase

25. Two-compartment model

29. Compartment Modeling - Stochastic Approach http://vam.anest.ufl.edu/simulations/fir storderstochasticsim.html#sim http://vam.anest.ufl.edu/simulations/se condorderstochasticsim2.html#sim

30. IV BOLUS Central K12 K21 K10 TWO COMPARTMENT MODEL Blood, Liver Kidney Muscle fatty Cp = Ae - 1t + Be - zt Elimination Peripheral

31. Blood flow to human tissues TissuePercent Body Weight Percent Cardiac Output Blood Flow (ml/100 g tissue/min) Adrenals 0.021550 Kidney 0.424450 Liver 2.025 Hepatic Portal 520 75 Brain 2.01555 Skin 7.055 Muscle (basal) 40.0153 Connective Tissue 7.011 Fat 15.021

32. Extravascular dose Dp Cp Vd k 10 kaka Site of absorption e.v. dose

33. Oral administration

34. Drugs appear to distribute in the body as if it were a single compartment. The magnitude of the drug’s distribution is given by the apparent volume of distribution (V d ). Vd = Amount of drug in body ÷ Concentration in Plasma PRINCIPLE (Apparent) Volume of Distribution: Volume into which a drug appears to distribute with a concentration equal to its plasma concentration

35. DrugL/KgL/70 kg Sulfisoxazole0.1611.2 Phenytoin0.6344.1 Phenobarbital0.5538.5 Diazepam2.4168 Digoxin7490 Examples of apparent Vd’s for some drugs