Optimal Antifungal ProphylaxisThe Case for Posaconazole

Oliver A. Cornely, MD, FIDSA

Dep. I for Internal MedicineHematology - Oncology

Infectious Diseases – Intensive Care

Center for Clinical TrialsBMBF 01KN0706

University of Cologne

Sources of information

• 2 RCT

• Institutional data

Leukemia Treatment Path

Newly diagnosed = Uncontrolled leukemia

Induce remission by „induction chemotherapy“

Remission achieved ?

Yes

No

Consolidate remission by „consolidation chemotherapy“

Posaconazole3x 200 mg

Fluconazole1x 400 mg

orItraconazole2x 200 mg

Number of Induction Chemotherapies

POS(n = 304)

FLU/ITZ(n = 298)

n (%)

1 174 (57) 182 (61)

2 96 (32) 89 (30)

≥3 34 (11) 27 (9)

Time to Systemic Antifungal Use

Kaplan-Meier analysis of the time to empiric systemic antifungal use within the 100-day phase showed a significant difference in favor of POS (P = .0235)

100

75

50

0

25

0 20 40 60 80 100

% w

ith

sys

tem

ic a

nti

fun

ga

l

Time From Randomization

PosaconazoleOther azole

Posaconazole – censoredOther azole – censored

Censoring time is the minimum of the last contact date and day 100

Posaconazole Prophylaxis Effectively Prevented Invasive Fungal Infections

P =.0009

7/304 25/298

2%

8%

0%

2%

4%

6%

8%

10%

12%

IFI During Prophylaxis

Inci

den

ce o

f IF

Is (

%) Posaconazole

FLU/ITZ

7 25

Clinical Response, n (%)Posaconazole

(n = 304)

Standard Azoles

(n = 298) P† 95% CI

Clinical success 195 (64) 160 (54)

Clinical failure* 109 (36) 138 (46) .009 –18.3% to –

2.6%

Proven or probable invasive fungal infection

7 (2) 25 (8) <.001 –9.7% to – 2.5%

Use of systemic antifungal for 4 consecutive days for suspected/probable/proven invasive fungal infection

68 (22) 101 (34) .002 –18.7% to –

4.3%

Related adverse event leading to study drug discontinuation

25 (8) 25 (8) 0.94 —

Use of IV study drug for 4 consecutive or 10 total days

6 (2) 12 (4) 0.14 —

Withdrawal from study for any reason and loss to follow-up

8 (3) 1 (<1) .02 0% to 4.2%

Clinical Success and Reasons for Failure

*Patients might have been classified as experiencing clinical failure for more than 1 reason. Clinical failure included patients randomly assigned but not treated (posaconazole, 7 [2%]; standard azoles, 6 [2%]). †Chi-square test.

Overall Mortality – Time to Death

log rank, P = .035

Pro

bab

ilit

y o

f S

urv

ival

1.00

0.75

0.50

0.00

0.25

0 20 40 60 80 100Days after Randomization

PosaconazoleFLU/ITZ

Censoring time is last contact or day 100.

Numbers Needed to TreatPrimary and Secondary Endpoints in the Neutropenia Trial

Cornely OA, Ullmann AJ. Clin Inf Dis 2008.

All diagnostic procedures applied – IFI still under diagnosed.

Posaconazole3x 200 mg

Fluconazole1x 400 mg

Ullmann AJ et al. NEJM 2007.

Incidence of Proven/Probable IFIs

0

5

10

15

20

25

30

Posaconazole Fluconazole

Nu

mb

er

of

IFIs

All IFIs Invasive Aspergillosis

P = .004

P = .001

While on treatment

7

22

3

17

All IFIs Invasive Aspergillosis

P = .074

P = .006

Primary time period112 days after randomization

27

16

7

21

Ullmann AJ et al. NEJM 2007.

Posaconazole Prophylaxis in Real LifeThe Cologne Institutional Experience

2003-2005 No changes in diagnostic and therapeutic

strategy

2006-2008 Posaconazole Prophylaxis

→ Two time periods for a historic comparison of AML/MDS

patients undergoing 1st induction chemotherapy

Current Approach to Febrile Neutropenia

Neutropenia >10 Days

Fever >72h or Galactomannan positive

Posaconazole Prophylaxis

Rüping MJGT et al. Drugs. 2008.

Neutropenia >10 Days

Fever >72h or Galactomannan positive

Posaconazole Prophylaxis

Empiric Treatment

CT

BAL

Rüping MJGT et al. Drugs. 2008.

Current Approach to Febrile Neutropenia

TargetedTreatment

Characteristics

Topical polyene

(N= 82)

Posaconazole

(N= 77)

P

Age (Years) Mean

Median

Range

52 14.1

54

18 – 76

54 13.5

55

19 – 75

NS*

Female – no. (%) 32 (39.0%) 42 (54.5%) NS†

Neutropenic Days Mean

Median

Range

31.2 12.99

28

5 – 89

32.8 11.54

32

10 – 66

NS*

G-CSF‡ (no. [%]) 43 (52.4%) 27 (35.1%) 0.037†

*P-test for independent samples (two-sided) †Fisher’s exact test (two-sided)‡Granulocyte colony stimulating factor

Endpoints

100= 6.4

19.5% – 3.9%

Other Clinical Endpoints

Pharmacokinetic Aspects

PK of Posaconazole – AML InductionPatient Characteristic P Value*

Age .4637

Sex .3242

Race .0028†

Baseline body weight .1716

Baseline BSA .1157

GGT .0184

Liver enzymes .4077

Mucositis .6409

Neutropenia .4575

Diarrhea <.0001

Vomiting .5561

H2 receptor antagonist use .5887

PPI use .0010*t-test.†White vs nonwhite. Cornely et al. ICAAC 2006.

Posaconazole Plasma Levels Were Similar in Patients With and Without IFIs

Krishna G, et al. Pharmacotherapy. 2008;28:1223-1232.

Posaconazole Plasma Concentrations in AML/MDSCologne Cohort

Posaconazole Distribution into Pulmonary Components: Steady State Levels in Healthy Volunteers

0.01

0.1

1

10

100

1000

10000

0 2 4 6 8 10 12 14 16 18 20 22 24

Po

saco

naz

ole

Co

nce

ntr

atio

n,

μg

/mL

Hours Following Last Dose

Alveolar cells

Pulmonary epithelial lining fluidPlasmaMIC90 Aspergillus spp

Conte JE et al. Antimicrob Agents Chemother. 2009;53:703-707.

Posaconazole Concentrations in Peripheral Blood Compartments

Farowski F et al. TIMM-4, Athens, 2009.

PBMC PMN RBC Plasma1

10

100

1000

10000

100000

***

***

*

PS

C c

on

cen

trat

ion

[mg

/mL

]

PBMC (n=23), PMN (n=20), RBC (n=22), plasma (n=23); *p=.01, unpaired t-test; ***p<.001

Posaconazole Prophylaxis – Undefined Areas

• Patient groups outside the RCTs– Remission consolidation chemotherapy– Neutropenic allogeneic SCT– Other neutropenic, e.g. aplastic anemia, CLL,

pallative AML or MDS

• Pharmacokinetics– Is there a cut-off plasma concentration?– Bridging with IV during periods of e.g. nausea

• Antifungal strategy– Persistent fever– Possible breakthrough IFI