1. Practical Pharmacokinetics
September 22, 1998

2. Fundamental pharmacokinetic concepts
Volume of distribution
Half life & first order elimination
Zero order elimination (capacity-limited)
Clearance
Bioavailability and area under the curve (AUC)
Urinary vs. liver elimination & first pass effect
Plasma protein binding
Drug accumulation
Two compartment behavior

3. Pharmacokinetic parameters (Katzung)
Oral availability (%)
Urinary excretion (%)
Bound in plasma (%)
Clearance (L/h/70 kg) *
Volume of distribution (L/70 kg)
Half life (h)
Effective concentrations (µg/ml, etc.)
Toxic concentrations (µg/ml, etc.) *says ‘convert to mL/min by multiplying by 16.6’ (really converts to mL/min/70 kg)

4. Pharmacokinetic parameters (G&G)
Availability (oral) (%)
Urinary excretion (%)
Bound in plasma (%)
Clearance (ml . min-1 . kg-1)
Volume of distribution (liters/kg)
Half life (hours)
Effective concentrations (µg/ml, etc.)
Toxic concentrations (µg/ml, etc.)

5. Dimensional analysis
A fancy way of saying. ‘pay attention to the units’ conc =123 ng/ml = µg/ml = 123 µg/liter CL = 4.56 liters * min-1 * kg-1 Vd = 78.9 liters …or… Vd = 1.12 liters/kg F = 42% …or… F = 0.42

6. Drug ADME (absortion, distribution, metabolism & excretion)

7. The body as a bathtub

8. Intermittent dosing

9. First order elimination
The rate of elimination is proportional to the concentration of the drug
There is a characteristic half life for elimination of the drug
Doubling the dosing rate doubles the concentration of the drug in the steady state (linear pharmacokinetics)

10. Elimination rate constant
Relationship between the rate of drug elimination and the total amount of drug in the body Quantification: Kelim (h-1) = /half life (h) = natural logarithm of 2

11. First Order Elimination and Clearance
Rate of elimination of the drug is proportional to its concentration. The proportionality is called the clearance (CL) Rate of elimination (mg/h) = CL (liters/h) * conc (mg/liter)

12. Clearance
The sum of all processes that eliminate a drug from the plasma (e.g., CL = CLliver + CLkidney + …)
Quantification: CL (liters/h) = rate of elimination (mg/h)/plasma conc (mg/liter)

13. A simple-minded view of the kidney nephron

14. A simple minded view of the liver

15. Volume of distribution (Vd)
Relationship between the total amount of drug in the body and the plasma concentration
Quantification: Vd(liters) = total drug (mg)/plasma conc (mg/liter)

16. General determinants of drug distribution

17. A small volume of distribution

18. General determinants of drug distribution

19. A large volume of distribution

20. Half life
Time required for elimination of half of the drug from the body Quantification: half life (h) = (0.693*Vd (liters))/CL (liters/h)

21. First order elimination
Half lives % remaining %eliminated

22. Vd? Half-life? (2 mg IV, 77 kg subject)

23. Vd? Half-life? (2 mg IV, 77 kg subject)
Half life = h ( to , 95% CI)

24. Vd? Half-life? (2 mg IV, 77 kg subject)
64 ng/ml = 64 µg/liter = mg/liter
Vd total = 2 mg/0.064 mg/liter = liters
Vd = liters/77 kg ~ 0.42 liters/kg

25. How to calculate a loading dose
The problem: fill the total volume of distribution with an appropriate initial concentration loading dose (mg) = Vd (liters) * initial target conc (mg/liter)

26. diazepam, pharmacokinetic parameters
Oral availability (%) (N/A)
Urinary excretion (%) 1
Bound in plasma (%) 99
Clearance (L/h/70 kg) *
Volume of distribution (L/70 kg) 77
Half life (h)
Effective concentrations (µg/ml, etc.) ng/ml
Toxic concentrations (µg/ml, etc.) ...

27. Calculating a bolus IV dose of diazepam for a patient, 100 kg (corrected)
Target concentration = 0.35 mg/liter
Total Vd = (100 kg) * (77 liters/70 kg) = 110 liters
Dose = 110 liters * 0.35 mg/liter = 38.5 mg

28. Time-concentration curves of diazepam following IV or oral administration of 38.5 mg in 100 kg patient (corrected)

29. Time-concentration curves of diazepam following IV or oral administration of 38.5 mg in 100 kg patient (corrected)

30. Zero-order (capacity-limited) elimination
Rate of drug elimination is independent of its concentration
Elimination process is saturated at plasma concentrations
Doubling the dosing rate more than doubles the concentration of drug - steady state not reached (non-linear pharmacokinetics)

31. Examples of drugs with zero-order or mixed elimination kinetics
ethanol
phenytoin
nifedipine

32. Time concentration curve of ethanol in a 70 kg human consuming 3 drinks per hour for 6 hours

33. Bioavailability
Fraction of drug absorbed into the systemic circulation from a given route of administration; usually the oral route.
Quantified: F = (AUC)oral/(AUC)IV (May be expressed as a fraction of 1 or as percent)

34. First pass effect
Destruction or elimination of a drug on its first pass by the liver and other absorption pathways
Drugs with major first pass effect (bioavailability) imipramine (40) lidocaine (35) morphine (24) propranolol (26)
Drug with little or no first pass effect (bioavailability) diazepam (100) clonidine (95) metronidazole (99) sulfamethoxazole (100)

35. Time-concentration curves of diazepam following IV or oral administration of 28.5 mg in 77 kg patient

36. Oral vs. I.V., dosing of dicloxacillin, bioavailability ~ 0.5

37. Time to peak concentration following oral administration of dicloxacillin

38. Accumulation
During repeated dosing the concentration of drug increases until the rate of elimination equals the rate of dosing (depends on half-life and dosing interval)
Quantification: accumulation factor# = 1/(1-fraction remaining*) #steady state compared to first dose level *at the end of the dosing interval

39. Lack of accumulation of dicloxacillin (half-life = 0
Lack of accumulation of dicloxacillin (half-life = 0.7 hours) given at 4 hour intervals

40. Accumulation of digoxin, 0.3 mg daily (half-life = 39 hours)

41. Accumulation of digoxin, 0.9 mg daily (half-life = 39 hours) (TOXIC)

42. digoxin, pharmacokinetic parameters
Oral availability (%)
Urinary excretion (%) 60
Bound in plasma (%) 25
Clearance (L/h/70 kg) * 7.8
Volume of distribution (L/70 kg) 440
Half life (h)
Effective concentrations (µg/ml, etc.) > 0.8 ng/ml
Toxic concentrations (µg/ml, etc.) > 2.0 ng/ml

43. Digitalization (loading dose, 0
Digitalization (loading dose, 0.44 mg) followed by maintenance digoxin, 0.3 mg/day

44. Approximate accumulation factor of a drug with first order kinetics

45. Advantages & disadvantages of long half-life
Once a day dosage or less
Easy to maintain plasma levels in therapeutic window
Missed doses are no big deal
If toxicity occurs, it is a long wait* *can accelerate removal of some drugs by dialysis

46. Advantages & disadvantages of short half life
Can dynamically titrate effects by I.V. infusion
If toxicity occurs, it is not long to wait
Multiple daily dosage or ...
May require a slow release dosage form
Difficult to maintain plasma levels in therapeutic window
Missed doses drop plasma levels below therapeutic

47. Time concentration curve of metoprolol, 25 mg every 6 hours (half life = 3.2 hours), peak/trough ~ 3

48. Approximate peak/trough ratios for a rapidly absorbed drug with first order kinetics

49. Time concentration curve of slow release metoprolol, 100 mg every 24 hours (half life = 3.2 h), peak/trough ~ 1.4

50. I.V. infusion

51. lidocaine, pharmacokinetic parameters
Oral availability (%)
Urinary excretion (%) 2
Bound in plasma (%) 70
Clearance (L/h/70 kg) *
Volume of distribution (L/70 kg) 77
Half life (h)
Effective concentrations (µg/ml, etc.) > mg/L
Toxic concentrations (µg/ml, etc.) > 6 mg/L

52. I. V. infusion of lidocaine (half life 1
I.V. infusion of lidocaine (half life 1.8 h), 100 mg/h without or with a bolus loading dose

53. Two compartments, initial distribution

54. Elimination of a drug exhibiting two compartment behavior

55. Two compartments, equilibrated, in terminal elimination phase

56. Displacement by sulfisoxazole of bilirubin from plasma protein binding

57. What is the Vd of quinidine in an 80 kg patient?
Katzung: Vd quinidine = 130 L/70 kg 80kg * 130/70 (L/70 kg) = ~ 149 L

58. How to predict steady state plasma concentration
Average concentration of drug in the steady state (Css) Quantification: Css (mg/liter) = (dosing rate (mg/h) * bioavailability)/CL (liters/h)

59. How to calculate dosing rate for a given target steady state plasma concentration
Dosing rate (average, may be given in divided doses, be sure to calculate for 24 hours, or etc.) Quantification: (dosing rate (mg/h) = Css (mg/liter) * CL (liters/h)/ bioavailability (F)

60. Pharmacokinetic model used for simulations