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 ?