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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 • Institutional data Leukemia Treatment Path Newly diagnosed = Uncontrolled leukemia Induce remission by „induction chemotherapy“ Remission achieved ? No Yes Consolidate remission by „consolidation chemotherapy“ Posaconazole 3x 200 mg Fluconazole 1x 400 mg or Itraconazole 2x 200 mg Number of Induction Chemotherapies POS (n = 304) FLU/ITZ (n = 298) 1 174 (57) 182 (61) 2 96 (32) 89 (30) ≥3 34 (11) 27 (9) n (%) Time to Systemic Antifungal Use % with systemic antifungal 100 75 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 Time From Randomization Posaconazole Other azole Posaconazole – censored Other azole – censored Censoring time is the minimum of the last contact date and day 100 100 Posaconazole Prophylaxis Effectively Prevented Invasive Fungal Infections Incidence of IFIs (%) P =.0009 12% 10% 8% 8% 6% 4% 2% 0% 2% 7 7/304 25 25/298 IFI During Prophylaxis Posaconazole FLU/ITZ Clinical Success and Reasons for Failure Posaconazole (n = 304) Standard Azoles (n = 298) Clinical success 195 (64) 160 (54) Clinical failure* 109 (36) P† 95% CI 138 (46) .009 –18.3% to – 2.6% 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 Clinical Response, n (%) Proven or probable invasive fungal infection 0% to 4.2% *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 Probability of Survival 1.00 0.75 log rank, P = .035 0.50 0.25 Posaconazole FLU/ITZ 0.00 0 20 40 60 Days after Randomization 80 100 Censoring time is last contact or day 100. Numbers Needed to Treat Primary and Secondary Endpoints in the Neutropenia Trial All diagnostic procedures applied – IFI still under diagnosed. Cornely OA, Ullmann AJ. Clin Inf Dis 2008. Posaconazole 3x 200 mg Fluconazole 1x 400 mg Ullmann AJ et al. NEJM 2007. Incidence of Proven/Probable IFIs Posaconazole 30 Number of IFIs 25 Fluconazole P = .074 27 P = .004 22 20 P = .006 P = .001 17 15 21 16 10 5 7 7 3 0 All IFIs Invasive Aspergillosis While on treatment All IFIs Invasive Aspergillosis Primary time period 112 days after randomization Ullmann AJ et al. NEJM 2007. Posaconazole Prophylaxis in Real Life The 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 Posaconazole Prophylaxis Fever >72h or Galactomannan positive Rüping MJGT et al. Drugs. 2008. Current Approach to Febrile Neutropenia Neutropenia >10 Days Posaconazole Prophylaxis Fever >72h or Galactomannan positive CT BAL Empiric Treatment Targeted Treatment Rüping MJGT et al. Drugs. 2008. Characteristics Age (Years) Topical polyene Posaconazole (N= 82) (N= 77) 52 14.1 54 13.5 Median 54 55 Range 18 – 76 19 – 75 32 (39.0%) 42 (54.5%) 31.2 12.99 32.8 11.54 Median 28 32 Range 5 – 89 10 – 66 43 (52.4%) 27 (35.1%) Mean Female – no. (%) Neutropenic Days G-CSF‡ (no. [%]) Mean *P-test for independent samples (two-sided) †Fisher’s exact test (two-sided) ‡Granulocyte colony stimulating factor P NS* NS† NS* 0.037† Endpoints 100 19.5% – 3.9% = 6.4 Other Clinical Endpoints Pharmacokinetic Aspects PK of Posaconazole – AML Induction Patient Characteristic *t-test. †White vs nonwhite. 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 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/MDS Cologne Cohort Posaconazole Distribution into Pulmonary Components: Steady State Levels in Healthy Volunteers Alveolar cells Pulmonary epithelial lining fluid Plasma MIC90 Aspergillus spp Posaconazole Concentration, μg/mL 10000 1000 100 10 1 0.1 0.01 0 2 4 6 8 10 12 14 16 18 20 22 24 Hours Following Last Dose Conte JE et al. Antimicrob Agents Chemother. 2009;53:703-707. Posaconazole Concentrations in Peripheral Blood Compartments * PSC concentration [mg/mL] 100000 10000 *** 1000 *** 100 10 1 PBMC PMN RBC Plasma 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. 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