Pharmacodynamics of Antifungals D. Andes University of Wisconsin, Madison, WI.
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Transcript of Pharmacodynamics of Antifungals D. Andes University of Wisconsin, Madison, WI.
![Page 1: Pharmacodynamics of Antifungals D. Andes University of Wisconsin, Madison, WI.](https://reader036.fdocuments.us/reader036/viewer/2022062806/5697bfdb1a28abf838cb0b93/html5/thumbnails/1.jpg)
Pharmacodynamics of Antifungals
D. Andes
University of Wisconsin, Madison, WI
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Value of Animal Models
Time course of drug concentrations at sites of infection
Time course of antimicrobial activity at sites of infection
Dose-response relationships
Correlation of PK/PD parameters with efficacy
Magnitude of PK/PD parameter required for efficacy
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Fungal Densities in Kidneys of Mice Treated with Various Fluconazole Total Doses
Administered in 1, 2, or 4 Divided Doses
Fungal Density (log10 cfu/g) Total Fluconazole
Dose (mg/kg) q24 q12 q6
p- value
3.5 5.79 5.78 5.79 0.684.0 5.70 5.69 5.71 0.594.5 5.64 5.56 5.62 0.345.0 5.48 5.44 5.41 0.465.5 5.46 5.25 5.43 0.32
Louie et al. AAC 42:1105-1109
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Relationship Between Outcome and Fluconazole Dosing Interval
24 Hr Total Dose (mg/kg)
0.1 1 10 100 1000
Lo
g 10
CF
U/K
idn
eys
5
6
7q 24 hq 12 hq 6 h
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Fluconazole In vivo PAE Against C. albicans
Time (hrs)
Lo
g 10
CF
U/K
idn
eys
3
4
5
6
7
8
Control12.5 mg/kg PAE 20.7 h3.125 mg/kg PAE 4.4 h
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Impact of Ravuconazole Dosing Interval on Efficacy Against C. albicans in a Neutropenic Murine Model
Total Dose (mg/kg)
1 10 100 1000
Lo
g 10
CF
U/T
hig
h
3
4
5
6
7
8
q 72 h - ED50 89 mg/kg
q 36 h - ED50 48 mg/kg
q 24 h -ED50 61 mg/kg
q 18 h -ED50 80 mg/kg
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Patterns of Antimicrobial Activity
Time-dependent killing and prolonged persistent effects (duration related to AUC)
Seen with triazoles
Goal of dosing regimen: optimize amount of drug
AUC/MIC major parameter correlating with efficacy
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Relationship Between 5-FC PK/PD and Efficacy
Time Above MIC (%)
0 20 40 60 80 100
Log
10 C
FU
/Kid
neys
2
3
4
5
6
7R2 = 85.0%
24 Hour AUC/MIC
1 10 100 1000
R2 = 77.3%
Peak/MIC
0.1 1 10 100 1000
R2 = 53.1%
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Patterns of Antimicrobial Activity
Time-dependent killing and minimal to moderate persistent effects
Seen with flucytosine
Goal of dosing regimen: optimize duration of exposure
Time above MIC major parameter correlating with efficacy
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Relationship Between Amphotericin B PK/PDP and Efficacy
Peak Level/MIC
0.01 0.1 1 10
Log
10 C
FU/K
idne
ys
2
3
4
5
6
7
8R2 = 93%
72 Hour AUC/MIC
10 100 1000
R2 =61%
Time Above MIC (%)
0 20 40 60 80 100
R2 = 82%
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Relationship Between HMR 3270 Peak/MIC, AUC/MIC, and T>MIC and Efficacy Against C. albicans in a Neutropenic Murine Model
Peak/MIC
0.3 1 3 10 33
Log
10 C
FU/K
idne
ys
-1
0
1
2
3
4
AUC/MIC
30 100 300 1000
T>MIC (%)
0 20 40 60 80 100
R2 = 98% R2 = 80% R2 = 65%
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Patterns of Antimicrobial Activity
Concentration-dependent killing and prolonged persistent effects
Seen with amphotericin B, echinocandins,
Goal of dosing regimen: maximize concentrations
AUC/MIC and Peak/MIC major parameters correlating with efficacy
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Relationship Between Fluconazole 24 h AUC/MIC and Outcome Against
C. albicans with Varying MICs
24 Hour AUC/MIC
1 10 100 1000 10000
Log
10 c
fu/k
idne
ys
5
6
7
K-1 MIC 0.5 mg/l 98-17 MIC 16.0 mg/l98-234 MIC 32.0 mg/l
bestauc/mic vs Col 12
ED50
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24 Hour AUC/MIC
1 10 100 1000 10000
Lo
g 10
cfu
/kid
ne
ys
5
6
7
K-1 MIC 0.5 mg/l 98-17 MIC 16.0 mg/l98-234 MIC 32.0 mg/lLouie et al MIC 0.5 mg/l
bestauc/mic vs Col 12
ED50
ED50
Relationship Between Fluconazole Data Sets: AUC/MIC and Outcome Against
C. albicans with Varying MICs
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Fluconazole vs Murine Candidiasis in Literature
Author Endpoint AUC/MIC Louie CFU/24 h ED50 44
Van ‘t Wout CFU/7 d ED50 11.2
Rogers 80% Survival/21 d 18
Louie et al. AAC 42:1105-1109Van ‘t Wout et al. AAC 33:147-151Rogers et al. AAC 30:418-422
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Fluconazole dose-response with 9C. albicans strains with a >2000-fold
susceptibility
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
0 20 40 60 80 100 120 140 160 180AUC:MIC
Lo
g C
FU
ch
ang
e fr
om
no
Rx
YEM10 (MIC=0.25; parent of YEM11) YEM11 (MIC=8; BENup)
YEM12 (MIC=1; parent of YEM13-Target) YEM13 (MIC=64; BENup-Target)
YEM14 (MIC=0.25; parent of YEM15) YEM15 (MIC=128; CDR1/CDR2up)YEM24 (MIC=0.125; Del CDR1/CDR2) YEM27 (MIC=0.06; Del CDR1&2, BEN, FLU1)
YEM30 (MIC=0.5; parent of 24 & 27) Fitted Function
Sorensen et. al. ICAAC 1999
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Correlation of Animal Fluconazole PK/PD to Clinical Trials and Susceptibility
Breakpoints
NCCLS Breakpoint
Dose mg/day
AUC mgxh/l AUC/BP MIC
Clinical Success
R 64 800 475 7 High failure
S-DD 16-32 400-800 240-475 15 > 90%
S 8 200 134 17 > 90%
Rex et al. CID 24:235-247Edwards et al. CID 25:43-59Brammer et al. RID 12(Suppl 3):318-326
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• 34 patients, all species
– Mean and median dose of 200 mg/day Success rates varied with MIC
MIC N Cure AUC/MIC Cure (95% )
< 8 (S) 22 11 17 50% (28-72%)
16-32 (SDD) 6 11 8-4 7% (0-64%)
> 32 (R) 6 0 2 0% (0-46%)
Clancy & Nguyen, IDSA 1998, #98
Fluconazole/Candidemia Correlation
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• 32 patients, all species– Non-HIV (41% underlying malignancy)– Deep-seated infection (66% Blood stream infection)– Dose of 400 mg/day– Success rates varied with MIC
MIC N Cure AUC/MIC %Cure
< 8 (S) 24 19 30 79
16-32 (SDD) 6 4 15-8 67
> 32 (R) 2 0 2 0
Lee et al. AAC 2000;44:2715-8
Fluconazole/Candidemia Correlation
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PD for fluconazole and Candida
• Translation to humans– If we use a target of 25, then
• Loosely:1x above MIC for 24 hr = required dose• 100 mg/day should treat up to 4 mg/l• 400 mg/day should treat up to 16 mg/l• 800 mg/day should treat up to 32 mg/l
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Comparative Efficacy of Ravuconazole Against 8 Strains of C. albicans
Strains 24-h ED50 24-h AUC/MIC Free 24-h AUC/MIC*
K-1 48.9 547 23.7
412 27.0 578 24.3
98-17 204 502 21.1
98-234 126 318 13.1
580 73.1 416 17.8
2512 34.2 390 16.4
2307 40.8 873 36.7
2183 41.8 238 10.0
MEAN SD 20.3 8.2
* p-value = 0.43
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Free Drug AUC/MIC
0.1 1 10 100 1000
Lo
g 10 C
FU
/Kid
ne
ysRelationship Between Magnitudue of Fluconazole and
Ravuconazole AUC/MIC and Efficacy Against C. albicans in a Murine Model of Disseminated Candidiasis
Total Drug AUC/MIC
1 10 100 1000 100003
4
5
6
7
8
RavuconazoleFluconazole
ED50
ED50
ED50
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Relationship Between the Free-Drug 24-h AUC/MIC Required to Achieve the ED50 or 80% Survival
for Triazoles and the Candida albicans MIC
Minimum Inhibitory Concentration (mg/L)
0.01 0.1 1 10 100
Fre
e D
rug
24
-h A
UC
/MIC
3
10
30
100
300
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Antifungal PK/PD Summary
Drug Pattern PAE PK/PD Magnitude
Fluconzole Static Long AUC/MIC 25
5-FC Static Modest T>MIC 25-50
AmB Cidal Long Peak/MIC 2
Echinocandin Cidal Long Peak/MIC 3-10
Sordarins ? ? AUC/MIC ?