1. Dosing Regimen Concepts: 2-C, MM, Individualization principles
Applications
Practice Problems
Discussion

2. Two Compartment Concepts
Infusion rate calculation ?
Same as for the one-compartment case:
Ko = CL x Cp,ss,desired V1 V2
k10
k12
k21 Ko
Loading dose calculation ?

3. V1 V2
k10
k12
k21
Duration of infusion

4. Saturable metabolism
FDM/ Ko
Cp,ss CL

5. Saturable metabolism CLlin = 1L/h Db CLsat
Fraction of dose eliminated by the saturable pathway as dose increases ?
KM = 2.22 mg/L
Vmax = 100 mg/h
CL = CLlin + CLsat
When Cp << KM, CL = 100/ = 46 L/h
When Cp >> KM, CL  1 L/h

6. Saturable metabolism: Practice problem #3Db
kr = 0.15 h-1
ksat
a. above what body level does the
t1/2 become dose dependent ?
b. What is the minimum half life ?
KM = 100 mg
Vmax = 25 mg/h
kr = 0.15 h-1
c. What would be the rate of elimination when the body level was 150 mg ?

7. DR Individualization principles
DRusual generally based upon population average values for PK parameters and boundaries of the therapeutic window:
FDM/ Ko
= CLusual x Cp,ss,desired
usual
For a patient having CLunusual, make a proportional adjustment in the DR:
FDM/ Ko
unusual
CLunusual
CLusual
usual =

8. CL Determinants - Hepatic
Css Css,u
Low E parenteral
all E enteral
High E parenteral:

9. High E, parenteral administration
fup
Total Cp
Free
Time

10. Oral administration
Total Cp
fup
Free
Time

11. Oral administration
Total Cp
Clint,u
Free
Time

12. For the situation described, indicate with an arrow whether the listed parameters would increase, decrease, or not change.
Drug CL
[mL/min]
fup fe
Situation A
300
0.5
0.2
renal disease reduces GFR to 25% of normal B
500
0.05
competitive displacement increases fup to 0.25
Drug CL V
t1/2 fe
FFP DR
p.o. A B         
 or   

13. For the situation described, indicate with an arrow whether the listed parameters would increase, decrease, or not change.
Drug CL
[mL/min] V
[L]
fup fe
Situation A
100 75
0.5
0.6
renal disease reduces GFR to 25% of normal B 50
0.05
competitive displacement increases fup to 0.15
Drug CL V
t1/2 fe
FFP DR
p.o. A B            

14. For a drug eliminated by hepatic metabolism and administered orally on a multiple dose regimen, the dosing rate should be changed when:
plasma protein binding is changed.
hepatic blood flow is changed.
the intrinsic unbound metabolic clearance is changed.
the volume of distribution is changed.
all of the above.

15. For which one of the following would it be appropriate to lower the therapeutic window (based on total Cp) for an hepatically eliminated drug administered p.o.
high E drug and QH is abnormally low.
low E drug and QH is abnormally low.
low E drug and fup is elevated.
low E drug and CLint,u is elevated.
high E drug and CLint,u is elevated.

16. The CLH value of this drug is 5 L/h and fup = 0. 025
The CLH value of this drug is 5 L/h and fup = Indicate with arrows the changes that would result from the change indicated.
CLH Css,av Css,u,av DR Q
 CLint,u
 fup            

17. The CLH value of this drug is 45 L/h and fup = 0. 025
The CLH value of this drug is 45 L/h and fup = Indicate with arrows the changes that would result from the change indicated. Route is i.m.
CLH Css,av Css,u,av DR Q
 CLint,u
 fup            