Use of Modelling for PKPD Studies in Infectious Diseases Joe Standing Infectious Diseases and...
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Transcript of Use of Modelling for PKPD Studies in Infectious Diseases Joe Standing Infectious Diseases and...
Use of Modelling for PKPD Studies in Infectious Diseases
Joe Standing
Infectious Diseases and Microbiology UnitUCL Institute of Child Health, London
ESPID May 20121
Outline
• Principles of PKPD in microbiology and infectious diseases
• Introduction to nonlinear mixed effects modelling
• Scaling pharmacokinetics between adults and children
2
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
3
Principles of antimicrobial PKPD
4
Principles of antimicrobial PKPD
5
In vitro PKPD
6
7
Principles of antimicrobial PKPD
8
Clinical data: Cmax/MICRATE OF CLINICAL RESPONSE VS. CMAX/MIC RATIO
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Clinical data: AUC/MIC
10
Clinical data: AUC/MIC
11
Clinical data T>MIC
12
Clinical evidence lacking…
Clinical data T>MIC
13
…although some promising findings in critically ill patients with Pseudomonas:
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 PAGE14
Be careful …
15
Antiviral PKPD
16
Standing et al 2012 AAC in press
Antiviral PKPD
17
HIV viral load/CD4
HIV viral load/CD4
Outline
• Principles of PKPD in microbiology and infectious diseases
• Introduction to nonlinear mixed effects modelling
• Scaling pharmacokinetics between adults and children
20
Variability
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Individual Drug Concentration vs Time
0
1000
2000
3000
4000
5000
6000
0 1 2 3 4 5 6 7 8
Time (hr)
Pla
sm
a C
on
ce
ntr
ati
on
(n
mo
l/L
)
Possible modelling approaches
22
Individual Drug Concentration vs Time
0
1000
2000
3000
4000
5000
6000
0 1 2 3 4 5 6 7 8
Time (hr)
Pla
sm
a C
on
ce
ntr
ati
on
(n
mo
l/L
)
- Naïve Pooled- Two-stage- Non-linear mixed effects
Nonlinear mixed effects modelling
• Mixed effects:
–Fixed effects, population typical values (e.g.: CLpop, VDpop, Kapop)
–Random effects
• Inter and intraindividual variability
• Residual variability
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)
C= Ka∙DVሺKa−Keሻ∙൫𝑒−Ke∙t −𝑒−Ka∙t൯
All models are wrong, some are useful
25
Using models
• Simulations
• Minimising utility functions
26
Outline
• Principles of PKPD in microbiology and infectious diseases
• Introduction to nonlinear mixed effects modelling
• Scaling pharmacokinetics between adults and children
27
“Children are not small adults”Kearns 2003
VS.
“Children are small adults”Tod 2008 and adults?
28
“Children are small adults”
• CL often better correlated with BSA than wt (Cawford 1950)
• BMR correlated with wt0.75 (Kleiber 1947)
29
“Children are small adults”
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“Children are small adults”
31
Scaling in PK: Tod et al 2008
• MF = maturation function• OF = organ function
32
Scaling in PK: Maturation
• Anderson 2010, Midazolam maturation
33
Outline
• Principles of PKPD in microbiology and infectious diseases
• Introduction to nonlinear mixed effects modelling
• Scaling pharmacokinetics between adults and children
34
35
Scaling in PK – Organ Function
• Ceriotti et al 2008
Note: Age in years
36