Liposomal amphotericin B: 20 years of clinical experience The body of knowledge and familiarity of use Malcolm Richardson PhD, FIBiol, FRCPath Associate Professor in Medical Mycology University of Helsinki Finland Malcolm Richardson PhD, FIBiol, FRCPath Associate Professor in Medical Mycology University of Helsinki Finland Downloded from

Antifungal Therapy: The Last 50 Years ABCD LAmB ABLC Terbinafine # of drugs Nystatin Amphotericin B Griseofulvin 5-FC Miconazole Ketoconazole Slide concept: J. Rex, M.D. and R Lewis Year Fluconazole Itraconazole Caspofungin Voriconazole Echinocandins under development Posaconazole 2006 “All drugs known to humans are poisons, only the amount or dose determine the effects.” Paracelsus, Downloded from

Candida here, Candida there, Candida everywhere George Bernard Shaw, 1903 Downloded from

Difficult to treat: Candida biofilms Downloded from

Difficult to treat: Aspergillus angioinvasion Downloded from

Refractory infection: invasive aspergillosis Downloded from

Amphotericin B Formulations: Safety and Efficacy from Preclinical Data Downloded from

A Classic Example Francis, J Inf Dis 1994; 169: Aspergillosis in neutropenic rabbits LAmB 5 LAmB 10 LAmB 1 cAMB 1 Control Cr Rise 0 mg/dl 3 mg/dl Control 2 mg/dl Toxicity, but with survival Downloded from

Amphotericin B Formulations: Safety from the Clinical Literature Downloded from

Nephrotoxicity of cAMB is Notable  LOS (10d)  Mortality $30,000/episode Bates, CID 2001;32:686 Average of ~30% Downloded from

Lipid Formulations are NOT Problem Free  Acute infusion-related reactions:  Chills, rigor, fever, phlebitis, hypotension, and arrhythmia  May be compound specific  cAMB > ABCD > ABLC > LAMB  Cumulative dose-related toxicity:  K & Mg wasting, arrhythmia, anaemia, renal failure  cAMB > ABCD > ABLC > LAMB  Overall, however  They are definitely safer than AmB-D  Acute infusion-related reactions:  Chills, rigor, fever, phlebitis, hypotension, and arrhythmia  May be compound specific  cAMB > ABCD > ABLC > LAMB  Cumulative dose-related toxicity:  K & Mg wasting, arrhythmia, anaemia, renal failure  cAMB > ABCD > ABLC > LAMB  Overall, however  They are definitely safer than AmB-D Downloded from

Amphotericin B Formulations: Efficacy from the Clinical Literature Downloded from

Data are somewhat scattered Data fall into two large groups  Febrile neutropenia: a fair bit of data  Good randomized data, great safety data  Salvage of proven IFI  Although mostly open-label, there are rather a lot of cases in the literature Data fall into two large groups  Febrile neutropenia: a fair bit of data  Good randomized data, great safety data  Salvage of proven IFI  Although mostly open-label, there are rather a lot of cases in the literature Downloded from

Open-Label Trials: 575 Proven IFI % Failure % Success (CR/PR) 49 Ostrosky-Zeichner, CID N= Mehta 1997 Mills 1994 Ng Oppenheim 1995 Ringden 1991 Tollemar 1992 Walsh 1998 Walsh 1999 Downloded from

Recent Data for Liposomal Amphotericin B Downloded from

Empirical Therapy- Febrile Neutropenia Studies Walsh, et al. NEJM 1999;340:764-71, Walsh, et al. NEJM 2002;346:225-34, Walsh, et al. NEJM 2004;351: Downloded from

LAmB for Candidaemia Response to LAmB C. albicans89% C. glabrata80% C. krusei86% Non-neutropenic90% Neutropenic80% CVC removed91% CVC not removed88% Ruhnke et al. ICAAC Biofilms! Downloded from

Characteristics of Drugs That Are Good Candidates for Flexible Dosing History of safe use Familiarization Predictable pharmacokinetics Concentration-dependent pharmacodynamics Slide concept: R. Lewis Downloded from

Empirical Antifungal Therapy for Febrile Neutropenia A key factor in selecting an antifungal drug for empirical therapy in febrile neutropenic patients is the drug’s activity against the fungal pathogens most likely to be involved in these patients. Downloded from

The AmBiLoad Study Downloded from

Received > 1 dose of study drug Not upgraded = excluded 105 Randomized = 339 patients Probable or Proven Eligibility not confirmed by DRB Possible DRB Confirmed = MITT 226 Qualified by investigators Upgraded to Proven or Probable 38 Downloded from

Underlying Conditions N (%) LAmB 3 mg N=107 Hematological Malignancies 1 99 (93) Controlled 36/99 (36) Uncontrolled 2 63/99 (64) Allo-SCT 17 (16) Other 3 8 (8) Neutropenia 4 at baseline 76 (71) Neutropenia 4 unresolved at EOT 40 (37) 1. Includes acute & chronic leukemia, lymphoma, myeloma, myelodysplastic syndrome 2. Absence of complete remission at study entry 3. Solid organ transplant, HIV, other conditions requiring chronic corticosteroid therapy 4. Neutropenia: ANC<500 cells/mm3 Downloded from

AmBiLoad Trial: Endpoints  Endpoints:  Overall response at investigator-determined EOT  Favorable = Complete + Partial responses  Unfavorable = Stable + Failure + Unevaluable  Survival at d14, EOT, 4 wks post-EOT and 12 weeks  Safety of 10 mg/kg/day dose compared to standard dose MITT population  Data Review Board confirmed all IFI cases and overall response assessments  Endpoints:  Overall response at investigator-determined EOT  Favorable = Complete + Partial responses  Unfavorable = Stable + Failure + Unevaluable  Survival at d14, EOT, 4 wks post-EOT and 12 weeks  Safety of 10 mg/kg/day dose compared to standard dose MITT population  Data Review Board confirmed all IFI cases and overall response assessments Cornely OA, et al, CID 2007 (in press) Downloded from

Overall Response at EOT N (%) AmBi-3mg N=107 Favorable Overall Response (FOR) at EOT 53 (50) CR1 (1) PR52 (49) Unfavorable Response Stable8 (7) Failure36 (34) Not evaluable10 (9) Duration of treatment, median (range): 3 mg: 15 days (1-60); No significant difference in overall response rates between the treatment arms Downloded from

Survival Alive / N (%) AmBi-3mg N=107 Day 14100/107 (94) EOT99/107 (93) 4 wks post-EOT (median Rx: d) 81/107 (76) 12 weeks76/106 (72) No significant difference in overall response rates between the treatment arms Downloded from

Safety  No unusual or previously unreported safety signals were seen in either treatment arm  Higher rates of nephrotoxicity, hypokalemia and drug discontinuations (statistically significant) were seen in 10 mg/kg/day arm compared to 3 mg/kg/day arm  Confirms safety profile of 3 mg/kg/day dose in this highly immunocompromised patient population  No unusual or previously unreported safety signals were seen in either treatment arm  Higher rates of nephrotoxicity, hypokalemia and drug discontinuations (statistically significant) were seen in 10 mg/kg/day arm compared to 3 mg/kg/day arm  Confirms safety profile of 3 mg/kg/day dose in this highly immunocompromised patient population Downloded from

% Herbrecht et al 1 Cornely et al 2 Voriconazole N=144 AmBisome 3mg/kg/d N=107 Total Haematological Malignancy (% excluding SCT) 82 (52)93 (76) Allo-SCT2616 Neutropenia*45 71 Neutropenia present at EOT NR37 Comparison to Other Studies: Patient Characteristics *Vori: ANC <500 within 14d of study entry; AmBiLoad: ANC <500 at study entry 1. Herbrecht R, et al. N Engl J Med. 2002; 347: Cornely O, et al. CID 2007 (in press) Downloded from

Putting AmBiLoad in context Voriconazole vs. cAMB AmBisome Survival at week 12 Downloded from

AmBisome Today  Extensive body of knowledge and history of use (familiarity)  Broad spectrum  First publication: 1990  Number of Medline entries: 481  Number of Google Scholar hits: 3,040  Number of patients treated: >460,000  Extensive body of knowledge and history of use (familiarity)  Broad spectrum  First publication: 1990  Number of Medline entries: 481  Number of Google Scholar hits: 3,040  Number of patients treated: >460,000 Downloded from

Five-year view Main focus: Invasive aspergillosis and emerging moulds  zygomycosis  scedosporiosis  fusariosis  Rationale  significant morbidity/mortality  relatively resistant to existing antifungals Prophylaxis Combination therapy Main focus: Invasive aspergillosis and emerging moulds  zygomycosis  scedosporiosis  fusariosis  Rationale  significant morbidity/mortality  relatively resistant to existing antifungals Prophylaxis Combination therapy Downloded from