LIPIDBASED ANTIFUNGAL AGENTS

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LIPID-BASED ANTIFUNGAL AGENTS

• Sevtap Arikan, MD
• Hacettepe University Medical School
• Ankara Turkey

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Fungi can infect..
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Fungal infections

• Superficial mycoses
• Subcutaneous mycoses
• Endemic (true systemic) mycoses
• Opportunistic mycoses

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Commonly isolated fungi

• Dermatophytes
• Thermally dimorphic fungi
• Candida
• Aspergillus
• Cryptococcus
• Zygomycetes
• ...

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An optimal antifungal drug has..

• Wide spectrum of activity
• Favorable pharmacokinetic profile
• Adequate in vivo efficacy
• Low rate of toxicity
• Low cost

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Amphotericin B is in clinical use since 1960

• A polyene macrolide
• Isolated from Streptomyces nodosus
• Insoluble in water
• Solubilized by sodium deoxycholate
• Available for IV use as amphotericin B
  deoxycholate (Fungizone)

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Amphotericin B binds to ergosterol and generates
pores

• Clin Microbiol Rev
  1999 12 501

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Amphotericin B is active in vitro against

• Candida spp.
• (including azole-resistant species)
• Aspergillus spp.
• Cryptococcus neoformans
• Mucor spp.
• Blastomyces dermatitidis
• Coccidioides immitis
• Histoplasma capsulatum
• Paracoccidioides brasiliensis

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Reduced susceptibility or resistance to
amphotericin B

• C. lusitaniae
• C. krusei
• C. neoformans
• Trichosporon spp.
• A. terreus
• Walsh et al. JCM 1990 28 1616
• Sutton et al. JCM 1999 37 2343
• Arikan et al. JCM 1999 37 3946 Arikan et al.
  JCM 2002 40 1406

• S. apiospermum
• Fusarium spp.
• C. carrionii
• F. pedrosoi
• ...

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Detection of amphotericin B resistance in vitro

• Technical problems
• The current NCCLS method may fail to discriminate
  resistant isolates from the susceptible ones

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But..

• In vivo amphotericin B resistance is observed
• Is usually due to the impaired immune system of
  the host

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Clinical Indications

• Candidiasis Coccidioidomycosis
• Aspergillosis Histoplasmosis
• Cryptococcosis Paracoccidioidomycosis
• Blastomycosis Sporotrichosis

Systemic mycoses
Febrile neutropenic patients unresponsive to
antibacterial therapy
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WHY LIPID FORMULATIONS?
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Because..

• ? Amphotericin B is toxic

• SIDE EFFECTS OF AMB
• Nephrotoxicity
• Acute infusion related reactions
• Hypopotassemia, anemia, hepatic
• dysfunction..

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LIPID amphotericin B formulations in use

• (ABLC Abelcet)
• (ABCD Amphocil or Amphotec)
• (L-AMB Ambisome)

Amphotericin B Lipid Complex
Amphotericin B Colloidal Dispersion
Liposomal Amphotericin B
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ABLC

• Ribbon-like particles
• Carrier lipids DMPC, DMPG
• J Liposome Res 1993 3 451

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ABCD

• 
  Disk-shaped particles
• Carrier lipid Cholesteryl sulfate
• J
  Pharmaceutics 1991 75 45

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The LIPOSOME..

• Hospital Practice 1992
  30 53

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L-AMB

• AMB incorporated in true unilamellar liposomes
• Carrier lipids HSPC, DSPG, cholesterol

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Comparative Pharmacokinetics
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Comparative in vitro activity

• AMB L-AMB
• (Anaissie et al. Eur J Clin Microb Infect Dis
  1991 10 665)
• AMB gt L-AMB
• (Pahls et al. J Infect Dis 1994 169 1057)
• AMB ABCD gt L-AMB ABLC
• (Oakley et al. AAC 1999 43 1264)

Candida spp.
Aspergillus spp.
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Comparative in vitro activityTwo questions..

• 1. Is testing the lipid formulation meaningful?
• 2. Are the in vitro results significant in vivo?

Done initially to verify maintanence of
antifungal activity The enhanced in VIVO activity
is the major concern
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Comparative in vivo efficacy

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Why are they occasionally more efficacious in
VIVO ??

• Exact mechanism unknown
• ? Selective uptake into RES
• ? Higher uptake, retension, and slow release by
  macrophages
• Storm et al. Eur J Clin Microbiol Infect Dis
  1997 1664
• Wasan et al. Eur J Clin Microbiol Infect Dis
  1997 16 81
• Mehta et al. J Infect Dis 1997 175 214

Macrophage
Liposome
Lysosome
Fusion
Liposome degradation
Endocytosis
Endocytic vesicle
Release from macrophage
Release in blood compartment
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Comparative nephrotoxicity
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Comparative rates of infusion related side effects
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More about the clinical use and toxicity

• Optimal doses remain unknown (1-7 mg/kg)
• Different modes of interaction of lipid
  formulations with plasma lipoproteins may play
  role in reduction of nephrotoxicity
• Wasan et al. AAC 1998 42 3146

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Major advantages of lipid AMB formulations

• Tolerable at high doses
• (3-7 mg/kg vs. 0.6-1 mg/kg for AMB)
• Significantly less toxic

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Major disadvantage of lipid AMB formulations is
their high primary cost

• Daily cost in USD
• for a 70 kg patient
• AMB (1 mg/kg)
• ABLC (5 mg/kg)
• ABCD (5 mg/kg)
• L-AMB (5 mg/kg)

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Lipid AMB formulations--Clinical indications

• NOT primary choices for any indication
• Used in cases who are refractory or intolerant to
  conventional AMB

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Other lipid AMB formulations under investigation

• AMB with immunoliposomes
• Otsubo et al. AAC 1998 41 40
• AMB with long circulating liposomes
• (PEG-L-AMB)
• Storm et al. Eur J Microb Infect Dis 1997 16
  64
• AMB cochleate
• Graybill et al. ICAAC 1999, abst. no. J-2009

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Nystatin

• A polyene derived from Streptomyces noursei
• Topical antifungal agent
• Toxic when administered systemically

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Liposomal nystatin is a systemic formulation

• Multilamellar liposome
• Carrier lipids DMPC, DMPG

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Liposomal Nystatin (Nyotran) is in late Phase
III trials

• Candida (including azole and some AMB-resistant
  strains)
• Aspergillus
• C. neoformans
• Trichosporon
• Fusarium
• Rhizopus
• Sporothrix
• ...
• Quindos et al. Eur J Clin Microb Infect Dis
  2000 19 645
• Arikan et al. JCM 2002 40 1406

IN VITRO ACTIVITY
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Liposomal nystatin may be used for salvage therapy

• Candidiasis
• Aspergillosis
• Offner et al. ICAAC 2000, abst. no. J-1102

IN VIVO EFFICACY
?A potential salvage agent in cases who do not
respond to currently available antifungal drugs
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Side effects of liposomal nystatin are usually
mild

• Hypokalemia
• Fever
• Dose-dependent nephrotoxicity
• Infusion-related side effects
• Rash
• Powles et al. ICAAC 1999, abst. no. LB-4
• Offner et al. ICAAC 2000, abst. no. J-1102

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Other lipid antifungal formulations under
investigation

• Liposomal ketoconazole
• Liposomal miconazole
• Liposomal hamycin

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Lipid antifungal agents..Many questions remain

• A great and promising progress in antifungal
  therapy..

• Comparative efficacywhich one is the best?
• Pharmacodynamics
• Mechanism of action
• Basis of improved therapeutic index
• Long term toxic effects
• Interactions with other drugs cytokines
• Role in first-line therapy
• Role in prophylactic therapy
• Initial optimal doses
• Pharmacoeconomics cost-effectivity