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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 [email protected]

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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

[email protected]

(based on a presentation given by L. Ostrosky-Zeichner, ISHAM Paris, 2006)


Antifungal therapy the last 50 years l.jpg

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

Slide concept: J. Rex, M.D. and R Lewis




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Difficult to treat:Aspergillus angioinvasion



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Amphotericin B Formulations: Safety and Efficacy from Preclinical Data


A classic example l.jpg

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



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Nephrotoxicity of cAMB is Notable

Average of ~30%

 LOS (10d)

 Mortality

$30,000/episode

Bates, CID 2001;32:686


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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



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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


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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.



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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.


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LAmB for Candidaemia

Biofilms!

Ruhnke et al. ICAAC 2005.


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Characteristics of Drugs That Are Good Candidates for Flexible Dosing

History of safe use

Familiarization

Predictable

pharmacokinetics

Concentration-dependent

pharmacodynamics

Slide concept: R. Lewis


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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.



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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


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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


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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)


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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);


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Survival

No significant difference in overall response rates between the treatment arms


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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


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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)


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Voriconazole vs. cAMB

AmBisome

Putting AmBiLoad in context

Survival at week 12

Survival at week 12


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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


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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


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