The General Concepts of Pharmacokinetics and Pharmacodynamics Hartmut Derendorf, PhD

1. The General Concepts of Pharmacokinetics and Pharmacodynamics Hartmut Derendorf, PhD University of Florida

2. PHARMACOKINETICS what the body does to the drug PHARMACODYNAMICS what the drug does to the body

3. Pharmacokinetics conc. vs time Pharmacodynamics conc. vs effect 0.4 1 Conc. Effect 0.0 0 25 Time 0 Conc (log) 10 -4 10 -3 PK/PD effect vs time 1 Effect 0 0 25 Time

4. Pharmacokinetics the time course of drug and metabolite concentrations in the body

5. Pharmacokinetics helps to optimize drug therapy: dose dosage regimen dosage form

6. What happens to a drug after its administration ? ("Fate of drug") Liberation Absorption Distribution Metabolism Excretion

7. Pharmacokinetic Parameters Clearance Volume of distribution Half-life Protein Binding Bioavailability

8. Clearance • quantifiesELIMINATION • is the volume of body fluid cleared per time unit (L/h, mL/min) • is usually constant

9. CL = Q·E Q Blood Flow E Extraction Ratio Clearance Eliminating Organ

10. Q Ci Co Eliminating Organ Clearance Parameters: Blood Flow, intrinsic clearance, protein binding Good prediction of changes in clearance Steady state

11. High-extraction drugs Low-extraction drugs

12. Clearance • Clearance can be calculated from • Excretion rate / Concentration e.g. (mg/h) / (mg/L) = L/h • Dose / Area under the curve (AUC) e.g. mg / (mg·h/L) = L/h

13. Total body clearance is the sum of the individual organ clearances CL = CLren + CLhep + CLother Clearance

14. Volume of Distribution Vd = X / Cp - quantifiesDISTRIBUTION - relates drug concentration (Cp) to amount of drug in the body (X) - gives information on the amount of drug distributed into the tissues

15. Apparent Volume of Distribution X X V V C1 C2 C1 > C2 V < Vd C1 = X / V V = X / C1 C2 = X / Vd Vd = X / C2

16. Volume of Distribution Dicloxacillin 0.1 L/kg Gentamicin (ECF)0.25 L/kg Antipyrine (TBW)0.60 L/kg Ciprofloxacin 1.8 L/kg Azithromycin 31 L/kg

17. Half-Life Half-life is the time it takes for the concentration to fall to half of its previous value Half-life is a secondary pharmacokinetic parameter and depends on clearance and volume of distribution

18. Half-Life k elimination rate constant CL clearance Vd volume of distribution

19. Protein Binding • reversibe vs. irreversible • linear vs. nonlinear • rapid equilibrium The free (unbound)concentration of the drug at the receptor site should be used in PK/PD correlations to make prediction for pharmacological activity

21. vascular space extravascular space binding to extracellular biological material plasma protein binding blood cell binding, diffusion into blood cells, binding to intracellular biological material tissue cell binding, diffusion into tissue cells, binding to intracellular biological material

22. Perfusate Dialysate Interstitium Capillary Cell Microdialysis

23. Microdialysis

24. Bioavailability - quantifies ABSORPTION f is the fraction of the administered dose that reaches the systemic circulation

25. BioavailabilityRate and Extent of Absorption

26. Compartment Models Parameters: Rate constants, intercepts Linear and nonlinear regression Complete concentration-time-profiles Steady-state and non-steady-state

27. Intravenous bolus One compartment model D k X E • Dose • Drug in the body • Drug eliminated

28. Intravenous bolus Plasma concentration (single dose) D Dose C0 Initial Concentration Vd Volume of Distribution

29. Intravenous bolus Semilogarithmic Plot Normal Plot

30. Intravenous bolus Plasma concentration (multiple dose, steady state) Trough Peak

31. Intravenous bolus Multiple Dose

32. Dose Drug at absorption site Drug in the body Drug eliminated First-order absorption One compartment model D f k k a A X E

33. Oral administration Plasma concentration (single dose)

34. Oral administration

35. Oral administration Average concentration (multiple dose, steady state)

36. Oral administration Multiple Dose

37. Dose Drug at absorption site Drug in the body Drug eliminated Zero-order absorption One compartment model D f R k 0 A X E

38. Constant rate infusion Plasma concentration (during infusion)

39. Constant rate infusion

40. Constant rate infusion Plasma concentration (steady state)

41. Dose Xc Drug in the central compartment Xp Drug in the peripheral compartment Drug eliminated Two-compartment model D k 10 Xc E k k 12 21 Xp

42. Two-compartment model Plasma concentration (single i.v. bolus dose) -phase: distribution phase -phase: elimination phase

43. Two-compartment model

44. Two-compartment model Volume of distribution Xc Xc Xc Xp Xp Xp initially steady state elimination phase

45. Two-compartment model

46. Short-term infusion

47. Xc Drug in the central compartment Xps Drug in the shallow peripheral compartment Xpd Drug in the deep peripheral compartment Three-compartment model Xp d k k 31 13 D k Xc E 10 k k 12 21 Xp s • Dose • Drug eliminated

49. Significance of Pharmacokinetic Parameters for Dosing Maintenance Dose Loading Dose Fluctuation Dosing Interval

50. Drug Delivery Pharmacokinetics Pharmacodynamics ? Biopharmaceutics ? PK-PD-Modeling