Use of Modelling for PKPD Studies in Infectious Diseases

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Presentation transcript:

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

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

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

Principles of antimicrobial PKPD

Principles of antimicrobial PKPD

In vitro PKPD

Principles of antimicrobial PKPD

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

Clinical data: AUC/MIC

Clinical data: AUC/MIC

Clinical data T>MIC Clinical evidence lacking…

Clinical data T>MIC …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 PAGE

Be careful …

Antiviral PKPD Standing et al 2012 AAC in press

Antiviral PKPD

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

Variability

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

Nonlinear mixed effects modelling 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)

All models are wrong, some are useful

Using models Simulations Minimising utility functions

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

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

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

“Children are small adults”

“Children are small adults”

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

Scaling in PK: Maturation Anderson 2010, Midazolam maturation

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

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