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

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

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

4. the time course of drug and metabolite concentrations in the body
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 Volume of distribution
Clearance
Volume of distribution
Half-life
Protein Binding
Bioavailability

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

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

10. Clearance Q Ci Co
Eliminating
Organ
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. Clearance
Total body clearance is the sum of the individual organ clearances
CL = CLren + CLhep + CLother

14. Volume of Distribution
Vd = X / Cp
- quantifies DISTRIBUTION
- 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 DistributionX X V C1 V C2
C1 > C2
V < Vd
C1 = X / V
V = X / C1
C2 = X / Vd
Vd = X / C2

16. Volume of Distribution
Dicloxacillin L/kg
Gentamicin (ECF) 0.25 L/kg
Antipyrine (TBW) 0.60 L/kg
Ciprofloxacin 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 plasma protein binding
blood cell binding,
diffusion into blood cells,
binding to intracellular biological material
tissue cell binding,
diffusion into tissue cells,
binding to extracellular biological material

22. Microdialysis
Interstitium
Capillary
Cell
Perfusate
Dialysate

23. Microdialysis

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

25. Bioavailability Rate 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 D k X E One compartment model Dose Drug in the body
Drug eliminated

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

29. Intravenous bolus
Normal Plot
Semilogarithmic Plot

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

31. Intravenous bolus
Multiple Dose

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

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

38. Constant rate infusion
Plasma concentration (during infusion)

39. Constant rate infusion

40. Constant rate infusion
Plasma concentration (steady state)

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

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. Three-compartment modelXp d k k 31 13 D k Xc 10 E k k 12 21 Xp s
Xc Drug in the central compartment
Xps Drug in the shallow peripheral compartment
Xpd Drug in the deep peripheral compartment
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 ?