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

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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

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Principles of antimicrobial PKPD

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Principles of antimicrobial PKPD

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In vitro PKPD

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Principles of antimicrobial PKPD

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

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Clinical data: AUC/MIC

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Clinical data: AUC/MIC

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Clinical data T>MIC

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Clinical evidence lacking…

Clinical data T>MIC

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…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 …

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Antiviral PKPD

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Standing et al 2012 AAC in press

Antiviral PKPD

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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

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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

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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

)

- 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

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Using models

• Simulations

• Minimising utility functions

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Outline

• Principles of PKPD in microbiology and infectious diseases

• Introduction to nonlinear mixed effects modelling

• Scaling pharmacokinetics between adults and children

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“Children are not small adults”Kearns 2003

VS.

“Children are small adults”Tod 2008 and adults?

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“Children are small adults”

• CL often better correlated with BSA than wt (Cawford 1950)

• BMR correlated with wt0.75 (Kleiber 1947)

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“Children are small adults”

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“Children are small adults”

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Scaling in PK: Tod et al 2008

• MF = maturation function• OF = organ function

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Scaling in PK: Maturation

• Anderson 2010, Midazolam maturation

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Outline

• Principles of PKPD in microbiology and infectious diseases

• Introduction to nonlinear mixed effects modelling

• Scaling pharmacokinetics between adults and children

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Scaling in PK – Organ Function

• Ceriotti et al 2008

Note: Age in years

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