High Dose AmBisome Treatment: what do we know?

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High Dose AmBisome Treatment what do we know?

• V-J Anttila
• Specialist in Infectious Diseases
• Helsinki University Central Hospital
• Finland
• January 2001

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Amphotericin B Deoxycholate

• 40 years clinical experience with drug
• Efficacy shown against most yeast and mould
  infections
• In yeast infections 0.5mg- gt0.7 mg/kg/day may be
  a sufficient dose
• ?0.7 mg/kg/day may be needed
• in unstable patients with candidemia
• in infections caused by strains with reduced
  susceptibility
• In mould infections higher doses needed
• dose should be tapered to the maximum tolerated
  level (e.g. 1-1.5 mg/kg/day)

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Amphotericin B Deoxycholate

• Toxicity of Amphotericin B deoxycholate major
  problem
• renal toxicity
• Lipid formulations of amphotericin B indicated in
  patients
• with impaired renal function
• who develop nephrotoxicity while receiving
  conventional amphotericin B

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Liposomal Amphotericin B

• Efficacy at least as good as with conventional
  amphotericin B
• Better tolerated than conventional amphotericin B
• Less nephrotoxicity compared with conventional
  amphotericin B
• 3 mg/kg/day used in most studies

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Liposomal Amphotericin BAmBisome

• High dose AmBisome treatment ?5 mg/kg/day-15
  mg/kg/day used at least in three published
  clinical studies
• Thakur CP Int J Antimicrobial Agents
  20011767-70
• Walsh et al ICAAC 1999 abstr 1640
• Buffels R et al ASH 2000 abstr 3395

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Liposomal Amphotericin BAmBisome

• Thakur CP A single high dose treatment of
  kala-azar with Ambisome (amphotericin B lipid
  complex) a pilot study. Int J Antimicrobial
  Agents 20011767-70
• 34 patients with parasitologically confirmed
  visceral leishmaniasis
• randomly divided
• 17 pts Ambisome 15 mg/kg as a single dose
• 17 pts amphotericin B deoxycholate 1 mg/kg for 20
  days

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Liposomal Amphotericin BAmBisome

• Thakur 2001 continued.
• Investigations and splenic aspirations were done
  on day 0, 21 and day 180
• All 34 patients had a clinical, parasitological
  and ultimate cure
• AmBisome was better tolerated than conventional
  amphotericin B
• Adverse events in group AmBisome
• shivering during infusion 3 (17 )
• nausea 1 (6 )
• rise in serum creatinine 0

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Liposomal Amphotericin BAmBisome

• Walsh TJ, Anaissie EJ, Goodman JL, Pappas P,
  Bekersky I, Buell DN. High-Dose Liposomal
  Amphotericin B in patients infected with
  aspergillosis and other filamentous fungi.
  Interscience Conference on Antimicrobial Agents
  and Chemotherapy (ICAAC) 1999 573
• phase I-II study of the safety, tolerance and
  plasma pharmacokinetics of Liposomal Amphotericin
  B (AmBisome )

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Liposomal Amphotericin BAmBisome

• Walsh et al ICAAC 1999 continued.
• Patients with infections due to Aspergillus spp
  and other filamentous fungi
• Dosage cohorts 7.5, 10.0, 12.5 and 15 mg/kg/day
• total number of patients 43 (8,10,7 and 19 per
  group, respectively)
• several patients extremely ill

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Liposomal Amphotericin BAmBisome

• Walsh et al ICAAC 1999 continued.
• AmBisome was tolerated at all doses
• Adverse events
• fever 8 (19)
• chills/rigors 5 (12 )
• doubling of baseline creatinine in 32 of all
  patients not dose related
• Success rates(CR, PR or stabilization) 21/31 (68
  ) intent-to-treat and 18/24 (75) in the
  evaluable (7 days on therapy) population

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Liposomal Amphotericin BAmBisome

• Buffels R et al. Efficacy and safety of high
  doses of liposomal amphotericin B (AmBisome ) in
  treatment of patients with invasive fungal
  infection. 42nd Annual Meeting of American
  Society of Hematolology (ASH) 2000 abstr 3395)
• 66 patients
• 35 adults, 21 children (?15 years), 10 neonates

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Liposomal Amphotericin BAmBisome

• Buffels et al. 2000 ASH continued.
• Dose of AmBisome
• 5-7.5mg/day 59 pts
• 7.5-10 mg/kg/day 3 pts
• gt10mg/kg/day 10 pts
• 41 had confirmed fungal infection
• 24 Candida
• 12 Aspergillus
• 4 Mucor
• 5 Others
• 8 pts had probable fungal infection
• 7 pts had possible fungal infection
• 10 patients were treated empirically

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Liposomal Amphotericin BAmBisome

• Buffels et al. AHA 2000 continued.
• Complete cure (CR) was obtained in 26/66 39.4
• Improvement (PR) 19/66 28.8
• CRPR 68
• 16 deaths were recorded 24.4
• 6 death caused by fungal infection 9.1
• In 2 patients the treatment was interrupted with
  a moderate increase of serum creatinine

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Liposomal Amphotericin BAmBisome

• High dose AmBisome treatment conclusion
• the dose can be increased up 15 mg/kg/day
• the tolerability of AmBisome 5-15 mg/kg/day is
  accetable in patients with life-threatening deep
  fungal infection
• some kidney toxicity may occur
• controlled studies of the efficacy and
  tolerability of high dose AmBisome are needed