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Malcolm Richardson PhD, FIBiol, FRCPath Associate Professor in Medical Mycology

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@helsinki.fi. Echinocandins under development

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Malcolm Richardson PhD, FIBiol, FRCPath Associate Professor in Medical Mycology

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  1. Liposomal amphotericin B: 20 years of clinical experienceThe body of knowledge and familiarity of use Malcolm Richardson PhD, FIBiol, FRCPath Associate Professor in Medical Mycology University of Helsinki Finland Malcolm.richardson@helsinki.fi Downloded from www.pharmacy123.blogfa.com

  2. Echinocandins under development Posaconazole “All drugs known to humans are poisons, only the amount or dose determine the effects.” Paracelsus, 1490 - 1541. Caspofungin Voriconazole ABCD LAmB ABLC Terbinafine Griseofulvin Amphotericin B Itraconazole Ketoconazole Fluconazole Nystatin Miconazole 5-FC Antifungal Therapy:The Last 50 Years # of drugs 18 16 14 12 10 8 6 4 2 0 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2005 2006 2000 Year Downloded from www.pharmacy123.blogfa.com Slide concept: J. Rex, M.D. and R Lewis

  3. Candida here, Candida there, Candida everywhere George Bernard Shaw, 1903 Downloded from www.pharmacy123.blogfa.com

  4. Difficult to treat: Candida biofilms Downloded from www.pharmacy123.blogfa.com

  5. Difficult to treat:Aspergillus angioinvasion Downloded from www.pharmacy123.blogfa.com

  6. Refractory infection: invasive aspergillosis Downloded from www.pharmacy123.blogfa.com

  7. Amphotericin B Formulations: Safety and Efficacy from Preclinical Data Downloded from www.pharmacy123.blogfa.com

  8. Toxicity, but with survival A Classic Example Cr Rise LAmB 5 0 mg/dl LAmB 10 3 mg/dl LAmB 1 cAMB 1 2 mg/dl Control Control Francis, J Inf Dis 1994; 169:356-68. Aspergillosis in neutropenic rabbits Downloded from www.pharmacy123.blogfa.com

  9. Amphotericin B Formulations: Safety fromthe Clinical Literature Downloded from www.pharmacy123.blogfa.com

  10. Nephrotoxicity of cAMB is Notable Average of ~30%  LOS (10d)  Mortality $30,000/episode Bates, CID 2001;32:686 Downloded from www.pharmacy123.blogfa.com

  11. 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 Downloded from www.pharmacy123.blogfa.com

  12. Amphotericin B Formulations: Efficacy fromthe Clinical Literature Downloded from www.pharmacy123.blogfa.com

  13. 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 Downloded from www.pharmacy123.blogfa.com

  14. Open-Label Trials: 575 Proven IFI N=279 24 226 16 30 23 26 31 % Failure 42 51 % Success (CR/PR) 49 74 58 69 77 Mehta 1997 Mills 1994 Ng 19958 Oppenheim 1995 Ringden 1991 Tollemar 1992 Walsh 1998 Walsh 1999 Ostrosky-Zeichner, CID 2003. Downloded from www.pharmacy123.blogfa.com

  15. Recent Data for Liposomal Amphotericin B Downloded from www.pharmacy123.blogfa.com

  16. 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;351:1391-402. Downloded from www.pharmacy123.blogfa.com

  17. LAmB for Candidaemia Biofilms! Downloded from www.pharmacy123.blogfa.com Ruhnke et al. ICAAC 2005.

  18. Characteristics of Drugs That Are Good Candidates for Flexible Dosing History of safe use Familiarization Predictable pharmacokinetics Concentration-dependent pharmacodynamics Downloded from www.pharmacy123.blogfa.com Slide concept: R. Lewis

  19. 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 www.pharmacy123.blogfa.com

  20. The AmBiLoad Study Downloded from www.pharmacy123.blogfa.com

  21. Randomized = 339 patients Received > 1 dose of study drug 331 Probable or Proven Possible 143 188 Upgraded to Proven or Probable 38 Not upgraded = excluded Qualified by investigators 105 Eligibility not confirmed by DRB 226 DRB Confirmed = MITT 25 201 Downloded from www.pharmacy123.blogfa.com

  22. UnderlyingConditions 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 www.pharmacy123.blogfa.com

  23. 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 Cornely OA, et al, CID 2007 (in press) Downloded from www.pharmacy123.blogfa.com

  24. Overall Response at EOT No significant difference in overall response rates between the treatment arms Duration of treatment, median (range): 3 mg: 15 days (1-60); Downloded from www.pharmacy123.blogfa.com

  25. Survival No significant difference in overall response rates between the treatment arms Downloded from www.pharmacy123.blogfa.com

  26. 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 Downloded from www.pharmacy123.blogfa.com

  27. 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; 347:408-415 2. Cornely O, et al. CID 2007 (in press) Downloded from www.pharmacy123.blogfa.com

  28. Voriconazole vs. cAMB AmBisome Putting AmBiLoad in context Survival at week 12 Survival at week 12 Downloded from www.pharmacy123.blogfa.com

  29. 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 Downloded from www.pharmacy123.blogfa.com

  30. 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 Downloded from www.pharmacy123.blogfa.com

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