1. Use of Modelling for PKPD Studies in Infectious Diseases
Joe Standing
Infectious Diseases and Microbiology Unit
UCL Institute of Child Health, London
ESPID May 2012

2. Outline Principles of PKPD in microbiology and infectious diseases
Introduction to nonlinear mixed effects modelling
Scaling pharmacokinetics between adults and children

3. Mathematical model
mathematical model n. a description or representation of something conceived or presented in mathematical terms. (OED) Population modelling with nonlinear mixed effects is recommended

4. Principles of antimicrobial PKPD

5. Principles of antimicrobial PKPD

6. In vitro PKPD

8. Principles of antimicrobial PKPD

9. Clinical data: Cmax/MIC
RATE OF CLINICAL RESPONSE VS. CMAX/MIC RATIO

10. Clinical data: AUC/MIC

11. Clinical data: AUC/MIC

12. Clinical data T>MIC
Clinical evidence lacking…

13. Clinical data T>MIC
…although some promising findings in critically ill patients with Pseudomonas:

14. Infusion length: T>MIC
Figure 3 Optimal infusion time plotted against MIC for meropenem. Green shaded area represents Eucast E.coli breakpoints of 2 and 8mg/L
Standing et al 2011 PAGE

15. Be careful …

16. Antiviral PKPD
Standing et al 2012 AAC in press

17. Antiviral PKPD

18. HIV viral load/CD4

19. HIV viral load/CD4

20. Outline Principles of PKPD in microbiology and infectious diseases
Introduction to nonlinear mixed effects modelling
Scaling pharmacokinetics between adults and children

21. Variability

22. Possible modelling approaches
Naïve Pooled
Two-stage
Non-linear mixed effects

23. Nonlinear mixed effects modelling
Fixed effects, population typical values (e.g.: CLpop, VDpop, Kapop)
Random effects
Inter and intraindividual variability
Residual variability

24. NONMEM NON linear Mixed Effects Modelling Structural model e.g.
Error model
Describes difference between observation and model prediction
Mixed effects:
Fixed effects (structure) and Random effects (error)

25. All models are wrong, some are useful

26. Using models
Simulations
Minimising utility functions

27. Outline Principles of PKPD in microbiology and infectious diseases
Introduction to nonlinear mixed effects modelling
Scaling pharmacokinetics between adults and children

28. “Children are not small adults”
Kearns 2003
VS.
“Children are small adults”
Tod 2008 and adults?

29. “Children are small adults”
CL often better correlated with BSA than wt (Cawford 1950)
BMR correlated with wt0.75 (Kleiber 1947)

30. “Children are small adults”

31. “Children are small adults”

32. Scaling in PK: Tod et al 2008 MF = maturation function
OF = organ function

33. Scaling in PK: Maturation
Anderson 2010, Midazolam maturation

34. Outline Principles of PKPD in microbiology and infectious diseases
Introduction to nonlinear mixed effects modelling
Scaling pharmacokinetics between adults and children

36. Scaling in PK – Organ Function
Ceriotti et al 2008
Note: Age in years