Table of Contents
PPT Slide
PPT Slide
Personnal presentation
Personnal presentation
Registering a new antibiotic : the issues
The ideal antibiotic ...
Will it always be ideal ?
Main causes of antibiotic failures...
Microbiological evaluation is (classically) static
Static techniques are (partly) inappropriate for
in vivo projections of sensitivities
Breakpoints introduce artificial (and not always
scientific) discontinuties in what is essentially a continuous distribution
PK / PD ...
PPT Slide
Pharmacokinetic/ Pharmacodynamics in Drug Development
and Evaluation of Efficacy
PPT Slide
PK/PD in drug develop-ment A view from FDA
Pharmacokinetic/ Pharmacodynamics and antibiotic
resistance...
PK/PD and drug devlop-ment A view from EMEA
Are PK / PD important in resistance ?
Just a few of them…
Pharmacokinetic/ Pharmacodynamics in Drug Development
and Evaluation
Pharmacokinetic/ Pharmacodynamics: What are the
goals ?
PK / PD of antibiotics in 2001 ?
PPT Slide
PPT Slide
The rest of the talk ...
Methods use to determine which are the pertinent
PK/PD parameters
Methods
In vitro dynamic models
Dilution models
Dilution models: a simple, useful system ...
Dilution models: more sophisticated ones...
PPT Slide
The goal is to mimic potentially useful and achievable
serum concentration variations
Why in vitro dynamic models ...
Methods
Animal models
Dissociating PK covariables
A typical animal model to establish which PK parameters
is associated with efficacy
PPT Slide
PPT Slide
PPT Slide
End-points of animal models
Relationship Between 24 Hr AUC/MIC and Mortality
for FQs in immunocompromised Animal Models with Gram (-) bacilli infection
(Craig, 2000) *
Relationship Between 24 Hr AUC/MIC and Mortality
for FQs in Immunocompetent Animal Models with Str. pneumoniae infection
(Craig, 2000) *
Known PK problems (with solutions) linked with
animal models
Known PD problems with animal models
Demonstrated advantages of animal models
Methods
PK/PD of fluoroquinolones in clinics
24h AUC / MIC : what were the data ?
24h AUC / MIC : what were the data ?
What is the 24h-AUC / MIC ratio (AUIC) ?
What is the 24h-AUC / MIC ratio (AUIC) ?
Modeling of the clinical data
Application to 24h AUC /MIC
AUC - - AUC /MIC - - Cmax/MIC - - T > MIC ?
Why are the conclusions of the clinical trials
apparently (sometimes and apparently) contradictory ?
Methods
Doctor or Regulator ?
PK/PD and population-based recommendations : the
issues
Examples of variations
Obtaining population cumulative frequencies
The rest of the talk ...
PK/PD patterns of antimicrobial activity
PPT Slide
PPT Slide
?-lactams : at least 50 % of the time above the
MIC...
PK / PD in action: what can you do with a model
?-lactam *
Improving ?-lactam efficacy by reducing the interval
?-lactams PK / PD and resistance
PK/PD patterns of antimicrobial activity (2 of
3) (after WA. Craig, 2000)
AUC / MIC - dependent antibiotics and resistance
AUC / MIC - dependent antibiotics and resistance
PK/PD patterns of antimicrobial activity (3 of
3) (after WA. Craig, 2000)
Aminoglycosides : obtain a peak !
PK / PD in action ...
PK /PD in action ...
PK PD in action ...
Fluoroquinolones : get both a peak and an AUC !
24h-AUC / MIC as a tool to determine acceptable
sensitivities to standard doses of FQ
Peak concentrations as a tool to determine acceptable
sensitivities to standard doses of FQ
Combining it all …(Peak and 24h-AUC / MIC) as predictors
of efficacy standard doses of FQ ...
Combining it all …(Peak and 24h-AUC / MIC) as predictors
of efficacy standard doses of FQ ...
Which value of AUC / MIC ?
To increase efficacy of FQ, you need to increase
both the AUC and the peak …
Breakpoints ??
The rest of the talk ...
What does Industry do ?
PPT Slide
The end of the talk ...
What can Regulatory Bodies require ? 1. Preclinical
data
What can Regulatory Bodies require ? 2. Clinical
data
What can Regulatory Bodies require ? 3. Package
insert
Do you do that in your own country ?
Better approaches in antibiotic approval ...
And remember: we are not so far away from one another
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