Post on 21-Jan-2016
Pharmacodynamics of Antifungals
D. Andes
University of Wisconsin, Madison, WI
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
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
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
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
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
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
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%
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
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%
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%
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
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
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
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
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
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
• 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
• 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
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
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
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
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
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 ?