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Pharmacodynamic Indices
Johan W. Mouton
Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands
JWM Grindelwald 30-01-2008
therapeutic success
Dosing should be such that the level of
antmicrobial activity is associated with a high
likelihood of therapeutic success.
DOSE
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Dose Finding - The Past
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How can PK/PD help here?
Efficacy of the drug
Potency of a drug
(MIC)
Exposure to the bug
In vivo
(PK)
JWM Grindelwald 30-01-2008
Lowest concentration
with no visible growth
after 18 hour incubation
MIC
10
PK
conc mg/l
8
6
X-acin 500 mg
4
.25
.5
1
2
4
2
0
0
4
8
12
16
20
24
MIC = 2 mg/L
time h
JWM Grindelwald 30-01-2008
8
Pharmacokinetic
Parameter (and Dose)
MIC
• Thus, we have to:
– Establish a relationship between the MIC in
vitro and concentrations in vivo (thus,
dosing regimens)
– Determine which dosing regimens are
optimal for Treatment in relation to the MIC
JWM Grindelwald 30-01-2008
Any idea where we are today?
No idea…
may be a mouse?
Might be a human,
though…
JWM Grindelwald 30-01-2008
PK/PD
• Neutropenic mouse thigh model
• Various doses and dosing regimens (q1 to q24)
• Outcome parameter: cfu counts after 24 h
• Plot PD parameter (AUC, Peak T>MIC) to effect
JWM Grindelwald 30-01-2008
K. pneumoniae, imipenem
3
2
dcfu
1
0
-1
-2
-3
10 0
10 1
10 2
auc
Based on data from Craig
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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
JWM Grindelwald 30-01-2008
K. pneumoniae, imipenem
3
2
dcfu
1
0
-1
-2
-3
10
100
time > mic
Based on data from Craig
JWM Grindelwald 30-01-2008
For beta-lactams, there is a direct
relation between
Time > MIC and efficacy
JWM Grindelwald 30-01-2008
8
8
6
6
10
8
cfu
10
cfu
cfu
10
6
4
4
4
2
2
2
0
0
0
20
40
60
T >mic %
80
100
0
0
1
2
log (peak) mg/l
1
2
log (auc) mg.h/l
Relationship between T>MIC , Peak, AUC and effect of levofloxacin
for S. pneumoniae in mice.
Each dot represents one mouse / dosingregimen.
Based on data from Scaglione & Mouton, 2001, 2003
JWM Grindelwald 30-01-2008
Log10 CFU/Thigh at 24 Hrs
PK/PD relationship is Class Dependent
10
8
6
levofloxacin
4
2
0
10
100
1000
1
10
Log10 CFU/Thigh at 24 Hrs
24-Hr AUC/MIC
1000 0
100
25
50
75
100
Time Above MIC
Peak/MIC
10
9
8
7
6
5
4
ceftazidime
3
2
Andes IJAA 2002
10
100
1000
24-Hr AUC/MIC
1
10
100
1000
Peak/MIC
0
25
50
75
100
Time Above MIC
JWM Grindelwald 30-01-2008
Relationship PkPd and Effect
T>MIC
Penicillins
Cephalosporins
Carbapenems
Monobactams
Tribactams
AUC
Aminoglycosides
Fluoroquinolones
Metronidazole
Lipopeptides
Ketolides
Macrolides
Clindamycin
Streptogramins
Glycopeptides Glycylcyclines
Oxazolidinones
Tetracyclines
Azoles
JWM Grindelwald 30-01-2008
Relationship AUC and effect
• What has the MIC to
do with this?
Scaglione et al., AAC 2003
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Fluconazole efficacy in mice
Dose vs MIC
Andes et al ISHAM 2003
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Pharmacokinetic parameters :
Measures of Exposure
PEAK
AUC and Peak are usually
linearly related to Dose
AUC
MIC
T > MIC
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'Normalizing pk/pd relationships'
Pharmacokinetic
parameter
MIC
Pharmacodynamic index
(AUC/MIC, Peak/MIC, T>MIC)
JWM Grindelwald 30-01-2008
Change in Log10 CFU/Kidneys
Fluconazole Pharmacodynamics Against Isogenic Strain Pairs of
Susceptible and Resistant C. albicans
2
R = 84%
0.0
1649 MIC 0.25
2183 MIC 4.0 - CDR
1002 MIC 1.0
2823 MIC 32 - MDR1, ERG 11
2-76 MIC 1.0
12-99 MIC 64 - CDR, MDR1, ERG 11
412 MIC 0.25
2307 MIC 128 - CDR, ERG 11
580 MIC 0.50
2438 MIC 32
FH1 MIC 1.0
FH5 MIC 4.0 - CDR
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
-3.5
0.1
1
10
100
24-h Total Dose
Andes et al ISHAM 2003
1000
0.01 0.1
1
10
100 100010000
24-hr AUC/MIC
JWM Grindelwald 30-01-2008
MIC
0.4
10
conc mg/l
8
0.2
0.1
0.0
6
4
2
0
-0.1
-6 -5 -4 -3 -2 -1
0
1
2
3
4
5
0
6
4
8
12
16
20
24
time h
2log fluconazole mg/L
In vivo CT profile
dynamic concentrations
In vitro effect
at fixed concentrations
1.0
0.8
prob cure
extinction
0.3
Response Curve
0.6
0.4
0.2
0.0
0
1
2
3
fluconazole (auc/mic)
JWM Grindelwald 30-01-2008
Fluconazole efficacy, OPC N=123
1.0
EC50
prob cure
0.8
R²
43.69
0.9938
0.6
0.4
0.2
0.0
0
1
2
3
log dose/mic L
Rodriguez-Tudela et al, AAC 2007
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Thus, 2 factors influence the value
of the pk/pd index:
MIC and its Errors/variation
Pharmacokinetics and its variation
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Why is the term pk/pd index used
instead of pk/pd parameter?
-a ratio (e.g.) of two independent
parameters, not a parameter
by itself
Mouton et al, J Antmicrob Chemother 2005.
Available from ISAP site
JWM Grindelwald 30-01-2008
The MIC
JWM Grindelwald 30-01-2008
MIC
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)
AT STATIC CONCENTRATIONS
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Kahlmeter et al, JAC 2003
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•Growth and/or kill rate dependent :
–strain, species
–medium composition, brand
–MH, supplements, ISO
–number of bacteria
–inoculum
–5.105 (CLSI) vs 105 (BSAC)
–temperature (35o vs 37o)
–growth phase
–CO2
–etc.
JWM Grindelwald 30-01-2008
2
log normalized MIC
0
-1
-2
-3
-4
-5
-6
0.0
microdilution
r²
0.9457
0.5
10
Mouton, icaac 2000
1.0
1.5
2.0
log MH dilution
JWM Grindelwald 30-01-2008
A reference MIC method has been described by ISO/CEN
Accepted by member States, pending final vote
ALL METHODS USED UN THE FUTURE SHOULD
BE VALIDATED AGAINST THIS METHOD
The method complies with CLSI and EUCAST
Several Posters at this ECCMID
JWM Grindelwald 30-01-2008
The reproducibility of the MIC is within 2 2-fold
dilutions. The variation introduced in the
AUC/MIC and Peak/MIC values by the MIC is
there for at least 0.5 tot 2 x the pk/pd index
value!
JWM Grindelwald 30-01-2008
MIC vs SC
(Stationary Concentration)
• SC= The concentration of antimicrobial
at which growth equals kill, i.e. no net
growth or kill at a certain point in time
• =NOT equal to MIC (which includes
time)
• Distinguish between MIC in vitro and in
vivo.
Mouton & Vinks Clin Pharmacokinet 2005 44:201-10
JWM Grindelwald 30-01-2008
MISCONCEPTION:
'Drug is active for a prolonged period of time,
and remains above the MIC long enough to….
The SC may be lower or higher than the MIC,
depending on its kill kinetics
In general the SC is lower, especially for concentration
dependent drugs
MIC
Mouton & Vinks Clin Pharmacokinet 2005 44:201-10
JWM Grindelwald 30-01-2008
PHARMACOKINETIC
parameters
JWM Grindelwald 30-01-2008
AUC
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, J Antmicrob Chemother 2005.
Available from ISAP site
JWM Grindelwald 30-01-2008
concentration
200
100
0
0
10
AUC 0-24 = 3033
AUC inf = 5100
AUC 0-24 sd = 1361
AUC inf sd =1700
20
30
40
time
Mg.h/L
JWM Grindelwald 30-01-2008
WHICH AUC?
• AUC or AUC
• Steady State?
• (log) trapezodeal rule?
• Derived ? (A/ +B/ or other)
0-24h

JWM Grindelwald 30-01-2008
AUC/MIC
Definition : The area under the concentration-time curve
over 24 hours in steady state divided by the MIC. ….
Note : ….For unbound fraction of the drug, use fAUC/MIC
Dimensions : no dimensions
Mouton et al, J Antmicrob Chemother 2005
Available from ISAP site
JWM Grindelwald 30-01-2008
AUIC
Definition :The Area under the inhibitory curve over
24 hours.
Note: the AUIC should be reserved for those cases
where actual inhibitory titers have been measured and
used in the calculations. The AUIC is not equal to the
AUC/MIC. See also Flaherty et al, AAC 1988;32(12):1825-29;
Hyatt JM et al AAC 1994;38(12):2730-7; Occhipinti DJ et al,
AAC 1997;41(11):2511-7.
Dimensions : none
Mouton et al, J Antmicrob Chemother 2005
Available from ISAP site
JWM Grindelwald 30-01-2008
Peak/MIC
Definition : the peak level divided by the MIC.
Dimensions : no dimensions.
Mouton et al, J Antmicrob Chemother 2005
Available from ISAP site
JWM Grindelwald 30-01-2008
WHICH PEAK LEVEL?
• After the 1st, 2nd or
simulation of 1.25 mg/kg q1h
concentration mg/L
2.0
simulated conc.
measured conc.
1.5
1.0
0.5
fig 2a
0.0
0
1
2
3
4
5
6
7
8
later dose?
time (h)
• If more than one
simulation 10 mg/kg +
1.25 mg/kg q1h
concentration mg/L
10
8
simulated conc.
6
4
2
fig 2b
0
0
4
8
12
16
20
24
time (h)
simulation 10 mg/kg +
1.25 mg/kg q1h
concentration mg/L
10
simulated conc.
8
6
4
compartment, the
peak level in
compartment 1, 2
or even 3?
fig 2c
2
0
0
4
8
12
16
20
24
time (h)
JWMal,
Grindelwald
Scaglione et
AAC30-01-2008
2003
fraction unbound
1.0
0.9
0.8
0.7
0.6
0.1
fu lev
fu cip
1
10
100
concentration mg/l
fig 1
Scaglione et al, AAC 2003
JWM Grindelwald 30-01-2008
Time > MIC
Definition : 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, J Antmicrob Chemother 2005
Available from ISAP site
JWM Grindelwald 30-01-2008
Variation in methods, definitions
Variation in estimation
Variation in population
JWM Grindelwald 30-01-2008
For all indices :
how are they determined
how are they calculated
what is the error?
Only when these questions have been
answered do we know the true impact and
value of the index.
JWM Grindelwald 30-01-2008