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

Liposomal amphotericin B: 20 years of clinical

experience

The body of knowledge and familiarity of use

Malcolm Richardson PhD, FIBiol, FRCPathAssociate Professor in Medical Mycology

University of Helsinki Finland

[email protected]

Malcolm Richardson PhD, FIBiol, FRCPathAssociate Professor in Medical Mycology

University of Helsinki Finland

[email protected]

Downloded from www.pharmacy123.blogfa.co

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Antifungal Therapy:The Last 50 Years

02468

1012141618

1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005

ABCDLAmBABLC

Terbinafine

# of drugs

Nys

tatin

Am

phot

eric

in B

Gris

eofu

lvin

5-FCMiconazole

Ketoconazole

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

Year

FluconazoleItraconazole

Caspofungin

Voriconazole

Echinocandinsunder developmentPosaconazole

2006

“All drugs known to humans are poisons, only the amount or dose determine the effects.”

Paracelsus, 1490 - 1541.


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Candida here, Candida there, Candida

everywhere

Candida here, Candida there, Candida

everywhereGeorge Bernard Shaw, 1903George Bernard Shaw, 1903


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Difficult to treat: Candida biofilms

Difficult to treat: Candida biofilms


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Difficult to treat: Aspergillus angioinvasion

Difficult to treat: Aspergillus angioinvasion


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Refractory infection: invasive aspergillosisRefractory infection: invasive aspergillosis


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Amphotericin B Formulations:

Safety and Efficacy from Preclinical Data

Amphotericin B Formulations:

Safety and Efficacy from Preclinical Data


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A Classic ExampleA Classic Example

Francis, J Inf Dis 1994; 169:356-68. 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


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Amphotericin B Formulations: Safety from the Clinical

Literature

Amphotericin B Formulations: Safety from the Clinical

Literature


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Nephrotoxicity of cAMB is Notable

Nephrotoxicity of cAMB is Notable

LOS (10d)

Mortality

$30,000/episode

Bates, CID 2001;32:686

Average of ~30%


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Lipid Formulations are NOT Problem Free

Lipid Formulations are NOT Problem Free

Acute infusion-related reactions:Chills, rigor, fever, phlebitis, hypotension, and

arrhythmiaMay be compound specificcAMB > ABCD > ABLC > LAMB

Cumulative dose-related toxicity:K & Mg wasting, arrhythmia, anaemia, renal failurecAMB > ABCD > ABLC > LAMB

Overall, howeverThey are definitely safer than AmB-D

Acute infusion-related reactions:Chills, rigor, fever, phlebitis, hypotension, and

arrhythmiaMay be compound specificcAMB > ABCD > ABLC > LAMB

Cumulative dose-related toxicity:K & Mg wasting, arrhythmia, anaemia, renal failurecAMB > ABCD > ABLC > LAMB

Overall, howeverThey are definitely safer than AmB-D


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Amphotericin B Formulations: Efficacy from the Clinical

Literature

Amphotericin B Formulations: Efficacy from the Clinical

Literature


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Data are somewhat scatteredData are somewhat scattered

Data fall into two large groupsFebrile neutropenia: a fair bit of data

Good randomized data, great safety data

Salvage of proven IFIAlthough mostly open-label, there are

rather a lot of cases in the literature

Data fall into two large groupsFebrile neutropenia: a fair bit of data

Good randomized data, great safety data

Salvage of proven IFIAlthough mostly open-label, there are

rather a lot of cases in the literature


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Open-Label Trials: 575 Proven IFIOpen-Label Trials: 575 Proven IFI

% Failure

% Success(CR/PR)49

Ostrosky-Zeichner, CID 2003.

74 6958 77

5126 42 31 23

N=279 226 3024 16

Mehta 1997Mills 1994Ng 19958Oppenheim 1995Ringden 1991Tollemar 1992Walsh 1998Walsh 1999


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Recent Data for Liposomal Amphotericin B

Recent Data for Liposomal Amphotericin B


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Empirical Therapy- Febrile Neutropenia Studies

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

LAmB for CandidaemiaLAmB for CandidaemiaResponse to LAmB

C. albicans 89%

C. glabrata 80%

C. krusei 86%

Non-neutropenic 90%

Neutropenic 80%

CVC removed 91%

CVC not removed 88%

Ruhnke et al. ICAAC 2005.

Biofilms!


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Characteristics of Drugs That Are Good Candidates for Flexible DosingCharacteristics of Drugs That Are

Good Candidates for Flexible Dosing

History of safe useFamiliarization

Predictablepharmacokinetics

Concentration-dependentpharmacodynamics

Slide concept: R. Lewis


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Empirical Antifungal Therapy for Febrile

Neutropenia

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.

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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The AmBiLoad StudyThe AmBiLoad Study


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Received > 1 dose of study drug

Not upgraded = excluded

105

Randomized = 339 patients

Probable or Proven

188

25

Eligibility not confirmed by

DRB

Possible

143

331

201

DRB Confirmed = MITT

226

Qualified by investigators

Upgraded to Proven or Probable

38


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Underlying Conditions Underlying Conditions

N (%)

LAmB 3 mg

N=107

Hematological Malignancies1

99 (93)

Controlled 36/99 (36)

Uncontrolled2 63/99 (64)

Allo-SCT 17 (16)

Other3 8 (8)

Neutropenia4 at baseline 76 (71)

Neutropenia4 unresolved at EOT

40 (37)

1. Includes acute & chronic leukemia, lymphoma, myeloma, myelodysplastic syndrome2. Absence of complete remission at study entry 3. Solid organ transplant, HIV, other conditions requiring chronic corticosteroid therapy4. Neutropenia: ANC<500 cells/mm3


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AmBiLoad Trial: EndpointsAmBiLoad Trial: EndpointsEndpoints:

Overall response at investigator-determined EOTFavorable = Complete + Partial responsesUnfavorable = 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 populationData Review Board confirmed all IFI cases and

overall response assessments

Endpoints: Overall response at investigator-determined EOT

Favorable = Complete + Partial responsesUnfavorable = 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 populationData Review Board confirmed all IFI cases and

overall response assessments

Cornely OA, et al, CID 2007 (in press)Downloded from


Overall Response at EOT Overall Response at EOT N (%)

AmBi-3mg N=107

Favorable Overall Response (FOR) at EOT

53 (50)

CR 1 (1)

PR 52 (49)

Unfavorable Response

Stable 8 (7)

Failure 36 (34)

Not evaluable 10 (9)Duration of treatment, median (range):3 mg: 15 days (1-60);

No significant difference in overall response rates between the treatment arms


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Survival Survival

Alive / N (%)AmBi-3mg

N=107

Day 14 100/107 (94)

EOT 99/107 (93)

4 wks post-EOT (median Rx: 14-15d)

81/107 (76)

12 weeks 76/106 (72)

No significant difference in overall response rates between the treatment arms


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SafetySafetyNo 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


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%

Herbrecht et al1

Cornely et al2

Voriconazole

N=144

AmBisome 3mg/kg/d

N=107

Total Haematological Malignancy(% excluding SCT)

82 (52) 93 (76)

Allo-SCT 26 16

Neutropenia* 45 71

Neutropenia present at EOT

NR 37

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; 347:408-4152. Cornely O, et al. CID 2007 (in press)Downloded from


Putting AmBiLoad in contextPutting AmBiLoad in context

Voriconazole vs. cAMB Voriconazole vs. cAMB AmBisomeAmBisome

AmBisomeAmBisome

Survival at week 12 Survival at week 12


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AmBisome TodayAmBisome Today

Extensive body of knowledge and history of use (familiarity)

Broad spectrumFirst publication: 1990Number of Medline entries: 481Number of Google Scholar hits: 3,040Number of patients treated: >460,000

Extensive body of knowledge and history of use (familiarity)

Broad spectrumFirst publication: 1990Number of Medline entries: 481Number of Google Scholar hits: 3,040Number of patients treated: >460,000


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Five-year viewFive-year view

Main focus: Invasive aspergillosis and emerging

moulds zygomycosis scedosporiosis fusariosis

Rationale significant morbidity/mortality relatively resistant to existing antifungals

ProphylaxisCombination therapy

Main focus: Invasive aspergillosis and emerging

moulds zygomycosis scedosporiosis fusariosis

Rationale significant morbidity/mortality relatively resistant to existing antifungals

ProphylaxisCombination therapy


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

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