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Optimal Antifungal Prophylaxis The Case for Posaconazole

Optimal Antifungal Prophylaxis The Case for Posaconazole. Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases – Intensive Care Center for Clinical Trials BMBF 01KN0706 University of Cologne. Sources of information. 2 RCT

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Optimal Antifungal Prophylaxis The Case for Posaconazole

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  1. Optimal Antifungal ProphylaxisThe Case for Posaconazole Oliver A. Cornely, MD, FIDSA Dep. I for Internal Medicine Hematology - Oncology Infectious Diseases – Intensive Care Center for Clinical Trials BMBF 01KN0706 University of Cologne

  2. Sources of information 2 RCT Institutional data

  3. Leukemia Treatment Path • Newly diagnosed = Uncontrolled leukemia Induce remission by „induction chemotherapy“ No Remission achieved ? Yes Consolidate remission by „consolidation chemotherapy“

  4. Fluconazole1x 400 mg • or • Itraconazole2x 200 mg • Posaconazole • 3x 200 mg

  5. Number of Induction Chemotherapies

  6. Time to Systemic Antifungal Use 100 75 % with systemic antifungal 50 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) 25 0 0 20 40 60 80 100 Time From Randomization Posaconazole Posaconazole – censored Other azole Other azole – censored Censoring time is the minimum of the last contact date and day 100

  7. Posaconazole Prophylaxis Effectively Prevented Invasive Fungal Infections P =.0009 Posaconazole 12% FLU/ITZ 10% 8% 8% Incidence of IFIs (%) 6% 4% 2% 2% 7 25 7/304 25/298 0% IFI During Prophylaxis

  8. 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.

  9. Overall Mortality – Time to Death 1.00 0.75 log rank, P = .035 Probability of Survival 0.50 0.25 Posaconazole FLU/ITZ 0.00 0 20 40 60 80 100 Days after Randomization Censoring time is last contact or day 100.

  10. Numbers Needed to TreatPrimary and Secondary Endpoints in the Neutropenia Trial All diagnostic procedures applied – IFI still under diagnosed. Cornely OA, Ullmann AJ. Clin Inf Dis 2008.

  11. Fluconazole1x 400 mg • Posaconazole • 3x 200 mg Ullmann AJ et al. NEJM 2007.

  12. Incidence of Proven/Probable IFIs Posaconazole Fluconazole 30 P = .074 27 25 P = .004 P = .006 22 20 P = .001 21 Number of IFIs 17 15 16 10 7 7 5 3 0 All IFIs Invasive Aspergillosis All IFIs Invasive Aspergillosis While on treatment Primary time period 112 days after randomization Ullmann AJ et al. NEJM 2007.

  13. 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

  14. Current Approach to Febrile Neutropenia Posaconazole Prophylaxis Fever >72h or Galactomannan positive Neutropenia >10 Days Rüping MJGT et al. Drugs. 2008.

  15. Posaconazole Prophylaxis Fever >72h or Galactomannan positive BAL Empiric Treatment Current Approach to Febrile Neutropenia Neutropenia >10 Days CT Targeted Treatment Rüping MJGT et al. Drugs. 2008.

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

  17. Endpoints

  18. Other Clinical Endpoints

  19. Pharmacokinetic Aspects

  20. PK of Posaconazole – AML Induction *t-test. †White vs nonwhite. Cornely et al. ICAAC 2006.

  21. Posaconazole Plasma Levels Were Similar in Patients With and Without IFIs Krishna G, et al. Pharmacotherapy. 2008;28:1223-1232.

  22. Posaconazole Plasma Concentrations in AML/MDSCologne Cohort

  23. Posaconazole Distribution into Pulmonary Components: Steady State Levels in Healthy Volunteers Alveolar cells Pulmonary epithelial lining fluid Posaconazole Concentration, μg/mL 10000 Plasma MIC90 Aspergillus spp 1000 100 10 Hours Following Last Dose 1 0.1 0.01 0 2 4 6 8 10 12 14 16 18 20 22 24 Conte JE et al. AntimicrobAgentsChemother.2009;53:703-707.

  24. Posaconazole Concentrations in Peripheral Blood Compartments PBMC (n=23), PMN (n=20), RBC (n=22), plasma (n=23); *p=.01, unpaired t-test; ***p<.001 Farowski F et al. TIMM-4, Athens, 2009.

  25. 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

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