pharmacodynamic indices
DESCRIPTION
Pharmacodynamic Indices. Johan W Mouton. Canisius-Wilhelmina Hospital Nijmegen, The Netherlands. PEAK / MIC AUC / MIC TIME > MIC. PEAK. AUC. MIC. TIME > MIC. PK/PD. Neutropenic mouse thigh model Various doses and dosing regimens (q1 to q24) Outcome parameter: cfu counts after 24 h - PowerPoint PPT PresentationTRANSCRIPT
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Canisius-Wilhelmina HospitalNijmegen, The Netherlands
Johan W Mouton
Pharmacodynamic Indices
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MIC
PEAK
PEAK / MICAUC / MICTIME > MIC
AUC
TIME > MIC
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PK/PD
• Neutropenic mouse thigh model
• Various doses and dosing regimens (q1 to q24)
• Outcome parameter: cfu counts after 24 h
• Plot PD index (AUC, Peak T>MIC) to effect
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K. pneumoniae, imipenem
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For K.pneumoniae, there is no clear relation
between total daily dose of imipenem and
efficacy in an in vivo model of infection
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K. pneumoniae, imipenem
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For beta-lactams, there is a direct
relation between
Time > MIC and efficacy
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Scaglione et al, ICAAC 1999
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Pharmacodynamic Indicespredictive for efficacy
T>MIC AUC (Peak)/MIC
Penicillins Aminoglycosides
Cephalosporins Fluoroquinolones
Carbapenems Metronidazole
Monobactams Daptomycin
Tribactams Ketolides
Clindamycin Macrolides
Oxazolidinones Azithromycin
Clindamycin Streptogramins
Glycopeptides
Glycylcyclines Tetracyclines
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Kill curves of ceftazidime, P. aeruginosa
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tobramycin
-2 -1 0 1 2 3-2
3
8
13
18
10log (conc tobramycin) mg/lki
llrat
e h
-1
meropenem
-3 -2 -1 0 1 2-2
-1
0
1
2
3
4
5
10log (conc meropenem) mg/l
killr
ate
h-1
Mouton & Vinks, 2003
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Kill curves of tobramycin, P. aeruginosa
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•Antibiotics showing increasing effect (killing) over a wide range of concentrations are called ‘concentration dependent’. In vivo effects are usually AUC and/or Peak related.
•Those with a limited range of increasing effect are called (wrongly) ‘concentration-independent’. In vivo effects are usually Time >MIC related.
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Pharmacodynamic index
Pharmacokinetic parameter MIC
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The MIC
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The MIC is a result of :
•kill over time (kill rate) by the antibiotic •growth over time (growth rate) •for a certain number of micro-organisms (the inoculum)
MIC
AT STATIC CONCENTRATIONS
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•Growth and/or kill rate dependent :–strain, species–medium composition, brand
–MH, supplements, ISO–number of bacteria–inoculum
–5.105 (NCCLS) vs 105 (BSAC)–temperature (35o vs 37o)–growth phase–CO2
–etc.
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0.0 0.5 1.0 1.5 2.0-6
-5
-4
-3
-2
-1
0
microdilution
e-test
10log MH dilution
2lo
g n
orm
aliz
ed M
IC
r²
2log mic
0.9457
2log etest
0.9507
Mouton, icaac 2000
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The MIC of the control strain should be within one two-fold dilution of the expected MIC
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PHARMACOKINETICparameters
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Definition :The Area under the Concentration-time curve over 24 hours.Note: ….. It should be stated how the AUC is determined : based on (log) linear trapezoideal rule, based on clearance, or based on microconstants.
Dimensions : concentration x time e.g. mg.h/L or g.h/mL
Mouton et al, Int J Antimicrob Agents april 2002
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AUC 0-24 = 3033 AUC inf = 5100AUC 0-24 sd = 1361AUC inf sd =1700
0 10 20 30 400
100
200
time
con
cen
trat
ion
Mg.h/L
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WHICH AUC?
•AUC 0-24h or AUC
•Steady State?
• (log) trapezodeal rule?
•Derived ? (A/ +B/ or other)
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Peak/MICDefinition : the peak level divided by the MIC.
Dimensions : no dimensions.
Mouton et al, Int J Antimicrob Agents april 2002
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WHICH PEAKLEVEL?
•After the 1st, 2nd or later dose?
•If more than one compartment, the peak level in compartment 1, 2 or even 3?
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simulation of 1.25 mg/kg q1h
0 1 2 3 4 5 6 7 80.0
0.5
1.0
1.5
2.0simulated conc.measured conc.
time (h)
con
cen
trat
ion
mg
/Lsimulation 10 mg/kg +
1.25 mg/kg q1h
0 4 8 12 16 20 240
2
4
6
8
10
simulated conc.
time (h)
con
cen
trat
ion
mg
/L
simulation 10 mg/kg + 1.25 mg/kg q1h
0 4 8 12 16 20 240
2
4
6
8
10
simulated conc.
time (h)
con
cen
trat
ion
mg
/L
fig 2a
fig 2b
fig 2c
Scaglione et al, icaac 1999
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0.1 1 10 1000.6
0.7
0.8
0.9
1.0
fu levfu cip
concentration mg/l
frac
tio
n u
nb
ou
nd
fig 1
Scaglione et al, unpubl.
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Time > MICDefinition : the % of time above the MIC over a period of 24 hours.Note : if the period is other than 24 h, this should be stated explicitly.
Dimensions : %.
Mouton et al, Int J Antimicrob Agents april 2002
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Concentration-time profile of beta-lactamVd = 20 L, Ka = 1.2 h-1, Ke = 0.3 h-1
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0.20
1.20
2.20
3.20
4.20
5.20
6.20
7.20
8.20
9.20
10.20
11.20
12.20
13.20
14.20
15.20
16.20
17.20
18.20
19.20
0.00
1.25
2.50
3.75
5.00
6.25
7.50
8.75
10.0
0
11.2
5
12.5
0
13.7
5
15.0
0
16.2
5
17.5
0
18.7
5
20.0
0
21.2
5
22.5
0
23.7
5
0.95-1.00
0.90-0.95
0.85-0.90
0.80-0.85
0.75-0.80
0.70-0.75
0.65-0.70
0.60-0.65
0.55-0.60
0.50-0.55
0.45-0.50
0.40-0.45
0.35-0.40
0.30-0.35
0.25-0.30
0.20-0.25
0.15-0.20
0.10-0.15
0.05-0.10
0.00-0.05
Conc
Time
Prob
Monte Carlo Simulation of beta-lactamVd = 20 L, Ka = 1.2 h-1, Ke = 0.3 h-1, VC=20%
4h
10h
Mouton, Int J Antimicrob Agents april 2002
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Mouton et al, Clin Pharmacokin 2000
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Mouton & Punt, JAC 2001
Amoxicillin/clavulanic acid
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For all indices :
how are they determinedhow are they calculated
what is the error?