The General Concepts of Pharmacokinetics and Pharmacodynamics

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 Bioavailability Protein Binding

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

20. BioavailabilityRate and Extent of Absorption

21. 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

23. 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

24. Perfusate Dialysate Interstitium Capillary Cell Microdialysis

25. Microdialysis

26. Pharmacokinetic profile of cefpodoxime (400 mg oral dose, n = 6)

27. Pharmacokinetic profile of cefixime (400 mg oral dose, n = 6) Mean ± SD

28. Pharmacokinetics

29. 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

30. Two-compartment model

31. Short-term infusion

32. 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

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

36. Questions • What are the effects of protein binding on antibiotic activity and interpretation of plasma levels? • What are the effects of a change in protein binding on unbound concentrations? • Why do we monitor post-distribution peaks as indicators of aminoglycoside activity? • Why do we monitor troughs as indicators of aminoglycoside toxicity? • How do you interpret a high tissue level of a macrolide?

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

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

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

40. Intravenous bolus Semilogarithmic Plot Normal Plot

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

42. Intravenous bolus Multiple Dose

43. 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

44. Oral administration Plasma concentration (single dose)

45. Oral administration

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

47. Oral administration Multiple Dose

48. 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

49. Constant rate infusion Plasma concentration (during infusion)

50. Constant rate infusion