1. Improvement in Dose Selection Through Clinical Applications of PK/PD in Antimicrobial Drug Development
Hartmut Derendorf, Ph.D.
University of Florida

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

3. PK PD
Serum
MIC

4. Pharmacokinetics
Problems:
Protein Binding
Tissue Distribution

6. 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

7. Microdialysis

8. Clinical Microdialysis
Cefpodoxime
400 mg po
Cefixime
400 mg po
Liu & Derendorf, JAC 50, 19 (2002)

9. Pharmacodynamics Problems: MIC is imprecise MIC is monodimensional
MIC is used as a threshold
When MIC does not explain the data, patches are used (post-antibiotic effect, sub-MIC effect)

10. Kill Curves flask reservoir tubing connector pump waste
Auto-dilution system

11. Piperacillin (2g and 4g) vs. E. coli
Dosing Interval
Piperacillin (2g and 4g) vs. E. coli
q24h
q8h
q4h
Nolting & Derendorf, Pharm. Res. 13, 91 (1996)

12. Kill Curves of Ceftriaxone
S. pneumoniae ATCC6303
MIC: 20 ng/mL
H. influenzae ATCC10211
MIC: 5 ng/mL

13. Kill Curves of Ceftriaxone
S. pneumoniae ATCC6303
MIC: 20 ng/mL
H. influenzae ATCC10211
MIC: 5 ng/mL

14. PK-PD Modeling Based on Kill Curves
Same PK
Same MIC
Same t>MIC
Same AUC/MIC
Same Cmax/MIC
Same k (Growth Rate)
Different EC50 (Sensitivity)
Different kmax (Maximum Kill Rate)
Control (CFU/mL)
Treated (CFU/mL)
Antibiotic concentration

15. Khunvichai & Derendorf, ICAAC 2001
Faropenem Daloxate
300 mg q12h
S. pneumo.
Fed
Fasted
Khunvichai & Derendorf, ICAAC 2001

16. Piperacillin in patients
Piperacillin serum and muscle levels in healthy patients and intensive care patients after single iv dose of 4g
Brunner et al, 2000

17. Piperacillin in patients
Piperacillin kill curves (MIC:  = 2 mg/l and =4 mg/l)
Sauermann et al, 2003

18. Summary
A simple comparison of serum concentration and MIC is usually not sufficient to evaluate the PK/PD-relationships af anti-infective agents.
Protein binding and tissue distribution are important pharmacokinetic parameters that need to be considered. Microdialysis can provide information on local exposure.
PK-PD analysis based on MIC alone can be misleading.
Microbiological kill curves provide more detailed information about the PK/PD-relationships than simple MIC values.

19. Conclusions
Intelligent PK/PD can help to streamline rational clinical dose selection
The final dose needs to be confirmed in a clinical trial

21. Acknowledgements Markus Müller Edgar Schuck Qi Liu Ping Liu
Teresa Dalla Costa
Amparo de la Peña
Ariya Khunvichai
Arno Nolting
Andreas Kovar
Kenneth Rand
Alistair Webb
Maria Grant