• A. Manufactured in the US by Versicor, Inc.
• B. SYNONYMS
  
  • 1. VER-002
  • 2. LY-303366
  • 3. V-Echinocandin

• A. SOLUBILITY
  
  • 1. Poorly soluble in water (less than 1 mg/mL). The octanol-water partition coefficient is 2 (Li et al, 2001).

• 1.3.1 NORMAL DOSE
  • A. INTRAVENOUS
    
    • 1. A single daily dose of 35 milligrams (mg) has been administered in esophageal CANDIDIASIS (Graybill, 2001).
    • 2. Anidulafungin has been given as a one-hour infusion (Graybill, 2001).
• 1.3.2 DOSAGE IN RENAL FAILURE
  • A. Limited data suggest no significant effect of renal impairment on pharmacokinetics (Graybill, 2001). However, this requires confirmation.
• 1.3.3 DOSAGE IN HEPATIC INSUFFICIENCY
  • A. Plasma levels of another echinocandin antifungal, caspofungin, are not significantly affected by moderate hepatic failure (Graybill, 2001). Although data for anidulafungin will likely be similar, no studies with this agent are available.

• 2.2.1 THERAPEUTIC
  • A. THERAPEUTIC DRUG CONCENTRATION
    
    • 1. In vivo (animal) or clinical correlations with in vitro data have not been investigated. Based on in vitro data, trough levels of at least 0.5 mcg/mL should be sufficient for activity against most Candida and Aspergillus strains.
  • B. TIME TO PEAK CONCENTRATION :
    
    • 1. ORAL : 6 to 7 hours (Chiou et al, 2000).
      • a. Value following oral doses of 100 to 1000 mg in healthy subjects. However, anidulafungin is not indicated for oral use due to poor bioavailability.

• 2.3.1 ABSORPTION
  • A. BIOAVAILABILITY (F) :
    
    • 1. ORAL :
      
      • a. A value of 5 to 10% (fasting state) has been reported in dogs (Li et al, 2001). Human data are unavailable.
  • B. EFFECTS OF FOOD : reduced absorption (Li et al, 2001).
    • 1. Based on animal data (30 to 75% decrease in AUC when given with food).
• 2.3.2 DISTRIBUTION
  • 2.3.2.1 DISTRIBUTION SITES
    • A. OTHER DISTRIBUTION SITES :
      
      • 1. TISSUES
        
        • a. Animal studies with anidulafungin (and other echinocandins) indicate extensive tissue distribution, including brain tissue (Chiou et al, 2000; Arathoon, 2001).
• 2.3.3 METABOLISM
  • 2.3.3.1 METABOLISM SITES AND KINETICS
    • A. LIVER, extent unknown (Graybill, 2001).
      • 1. Metabolic pathways have not been clearly defined. However, metabolism does not appear to involve the cytochrome P450 isozyme system (Graybill, 2001).
      • 2. In healthy subjects, cyclosporine had no significant effect on anidulafungin pharmacokinetics (Anon, 2002), whereas caspofungin levels may increase during combined therapy (Graybill, 2001).
• 2.3.5 HALF LIFE
  • 2.3.5.1 PARENT COMPOUND
    • A. ELIMINATION HALF-LIFE :
      
      • 1. After oral doses (up to 1000 mg), an elimination half-life of about 30 hours has been reported in healthy subjects (Chiou et al, 2000). Half-life data following intravenous use have not been made available.

• A. Prior hypersensitivity to anidulafungin

• A. Patients with prior hypersensitivity to other echinocandins (micafungin, caspofungin) (enhanced risk of sensitivity)
• B. Moderate-to-severe liver disease (potential for enhanced toxicity)
• C. Pregnancy (animal/human data unavailable)
• D. Breastfeeding period (animal/human data unavailable)

• 3.3.12 OTHER
  • A. OVERDOSE
    
  • B. ADVERSE EFFECTS - GENERAL
    
    • 1. Anidulafungin is reportedly well-tolerated, with minimal propensity for hematologic or renal toxicity (Graybill, 2001; Chiou et al, 2000). However, specific adverse-effect data from clinical studies have not been made available.

• 4.1.1 THERAPEUTIC
  • A. LABORATORY PARAMETERS
    
    • 1. Culture and sensitivity (C/S) prior to therapy; repeat cultures after treatment in selected patients
  • B. PHYSICAL EXAMINATION
    
    • 1. Clinical/radiographic evidence of improvement of fungal infection
    • 2. Endoscopic evaluation in esophageal candidiasis
• 4.1.2 TOXIC
  • A. LABORATORY PARAMETERS
    
    • 1. White count with differential, hemoglobin, hematocrit, liver function tests, renal function tests periodically
  • B. PHYSICAL EXAMINATION
    
    • 1. Signs/symptoms of toxicity, including fever, rash, phlebitis, persistent diarrhea

• A. Like caspofungin, anidulafungin has good activity against Candida spp., Aspergillus spp., and Pneumocystis carinii, and is similar to caspofungin for use in immunocompromised patients with superficial or disseminated candidiasis (primarily in azole or amphotericin B resistance) and aspergillosis (mainly infections resistant to amphotericin B or itraconazole). It may be especially useful in azole-refractory patients with renal impairment or failure. Disadvantages of anidulafungin are its lack of activity against Cryptococcus neoformans and possibly Candida parapsilosis, and poor oral bioavailability, which necessitates intravenous administration; these negative features are shared by caspofungin. One potential advantage of anidulafungin over caspofungin is lack of an interaction with cyclosporine, indicating no need for dose adjustment in transplant patients; however, this study was performed in healthy subjects, and studies with multiple doses in patients are needed to confirm this benefit.
• B. Direct comparisons with caspofungin are needed to determine any clinically relevant advantages of anidulafungin. Efficacy results of phase III studies comparing the drug to amphotericin B and fluconazole are also essential in addressing the role of this agent.

• A. MECHANISM OF ACTION
  
  • 1. Anidulafungin is an antifungal agent derived from echinocandin B; it is available only for parenteral administration (Arathoon, 2001; Ernst et al, 1997).
  • 2. Anidulafungin and other echinocandins are cyclic lipopeptides that interfere with formation of cell-wall glucan polymers via noncompetitive inhibition of (1,3)-beta-D-glucan synthase; glucan polymers are an essential component of the cell wall of many pathogenic fungi (Zhanel et al, 1997; Moore et al, 2001; Graybill, 2001; Arathoon, 2001).
• B. SPECTRUM OF ACTIVITY
  
  • 1. In vitro, anidulafungin is highly active against Candida albicans and other Candida spp., including fluconazole-resistant strains, with a minimum inhibitory concentration against 90% of strains (MIC-90) of 0.01 to 1 microgram/milliliter (mcg/mL) (usually less than 0.25 mcg/mL) (Zhanel et al, 1997; Roling et al, 2002; Marco et al, 1998; Cuenca-Estrella et al, 2000). Activity is rapid, with a high kill-rate for Candida spp. within 5 minutes of exposure (Moore et al, 2001; Graybill, 2001). However, C. parapsilosis has been less sensitive in most studies (MIC-90 up to 5 mcg/mL) (Zhanel et al, 1997; Espinel-Ingroff, 1998). Somewhat higher MICs have also been reported for Candida isolates from the lower gastrointestinal tract of seriously-ill patients (0.25 to 4 mcg/mL) (Zhanel et al, 1998).
  • 2. Anidulafungin is also active against most Aspergillus spp. (less than 0.1 mcg/mL) and trophic and cystic forms of Pneumocystis carinii (Arathoon, 2001; Chiou et al, 2000; Zhanel et al, 1997; Espinel-Ingroff, 1998). It has demonstrated low or no in vitro activity against Cryptococcus neoformans, Blastomyces dermatitidis, Fusarium spp., Sporothrix schenckii, Rhizopus spp, or Histoplasma capsulatum (Espinel-Ingroff, 1998; Zhanel et al, 1997; Roling et al, 2002; Chiou et al, 2000).
  • 3. Anidulafungin is not uniformly fungicidal, and the growth medium influences in vitro activity (Klepser et al, 1997; Graybill, 2001; Klepser et al, 1998), explaining the variation in some MIC values reported above. MIC values have been lower with use of the AM3 medium compared to the RPMI medium (Klepser et al, 1997). In vivo correlations with in vitro MICs in these media are needed. Some investigators suggest that an 80% reduction in visible growth should be used as the endpoint for susceptibility determinations in RPMI media (Klepser et al, 1998).
  • 4. In animal models (including immunocompromised animals) anidulafungin has shown activity in superficial and disseminated candidiasis, P. carinii pneumonia, and aspergillosis (pulmonary and disseminated) (Arathoon, 2001). It has been effective in fluconazole-resistant esophageal candidiasis (immunocompromised rabbits) and prolonged survival in amphotericin B-resistant invasive A. fumigatus infection (neutropenic mice) (Chiou et al, 2000; Arathoon, 2001)
• C. REVIEW ARTICLES
  
  • 1. General discussion of older and newer antifungal agents, including anidulafungin (de Pauw, 2000).
  • 2. Treatment of invasive aspergillosis (Perea & Patterson, 2002).
  • 3. Mechanisms, pharmacokinetics, and efficacy of the echinocandin antifungal agents (Arathoon, 2001).

• A. ESOPHAGEAL CANDIDIASIS
  
  • 1. OVERVIEW :

    
    FDA APPROVAL:  Adult, no; pediatric, no
    EFFICACY:  Adult, effective
    DOCUMENTATION:  Adult, fair
    

  • 2. SUMMARY :

    
     - Effective in limited studies
    

  • 3. ADULT :
    
    • a. Oral therapy with anidulafungin has been associated with low efficacy in candidal esophagitis (Graybill, 2001), likely related to poor oral bioavailability.
    • b. Limited, unpublished phase II data have suggested the efficacy of intravenous anidulafungin (Anon, 2001; Graybill, 2001). With once-daily infusions for up to 3 weeks, response rates of about 80% (endoscopic improvement) have been reported. Details of these studies are unavailable.
    • c. Direct comparisons with fluconazole, amphotericin B, and caspofungin are needed to address the role of anidulafungin.

1. Anon: Versicor moves lead product into pivotal phase III program. BioWorld Today March 23, 2001.

2. Anon: Versicor announces study results that support competitive advantage for anidulafungin. Doc Guide May 1, 2002; pp 1-3. Available at: http://www.docguide.com.

3. Arathoon EG: Clinical efficacy of echinocandin antifungals. Curr Opin Infect Dis 2001; 14:685-691.

4. Chiou CC, Groll AH & Walsh TJ: New drugs and novel targets for treatment of invasive fungal infections in patients with cancer. Oncologist 2000; 5:120-135.

5. Cuenca-Estrella M, Mellado E, Diaz-Guerra TM et al: Susceptibility of fluconazole-resistant clinical isolates of Candida spp. to echinocandin LY303366, itraconazole and amphotericin B. J Antimicrob Chemother 2000; 46:475-477.

6. de Pauw B: Is there a need for new antifungal agents? Clin Microbiol Infect 2000; 2:23-28.

7. Ernst ME, Klepser ME, Wolfe EJ et al: Antifungal dynamics of LY 303366, an investigational echinocandin B analog, against Candida ssp. Diagn Microbiol Infect Dis 1996; 26:125-131.

8. Espinel-Ingroff A: Comparison of In vitro activities of the new triazole SCH56592 and the echinocandins MK-0991 (L-743,872) and LY303366 against opportunistic filamentous and dimorphic fungi and yeasts. J Clin Microbiol 1998; 36:2950-2956.

9. Graybill JR: The echinocandins, first novel class of antifungals in two decades: will they live up to their promise? Int J Clin Pract 2001; 55:633-638.

10. Klepser ME, Ernst EJ, Ernst ME et al: Evaluation of endpoints for antifungal susceptibility determinations with LY303366. Antimicrob Agents Chemother 1998; 42:1387-1391.

11. Klepser ME, Ernst EJ, Ernst ME et al: Growth medium effect on the antifungal activity of LY 303366. Diagn Microbiol Infect Dis 1997; 29:227-231.

12. Li C, Fleisher D, Li L et al: Regional-dependent intestinal absorption and meal composition effects on systemic availability of LY303366, a lipopeptide antifungal agent, in dogs. J Pharm Sci 2001; 90:47-57.

13. Marco F, Pfaller MA, Messer SA et al: Activity of MK-0991 (L-743,872), a new echinocandin, compared with those of LY303366 and four other antifungal agents tested against blood stream isolates of Candida spp. Diagn Microbiol Infect Dis 1998; 31:33-37.

14. Moore CB, Oakley KL & Denning DW: In vitro activity of a new echinocandin, LY303366, and comparison with fluconazole, flucytosine and amphotericin B against Candida species. Clin Microbiol Infect 2001; 7:11-16.

15. Perea S & Patterson TF: Invasive Aspergillus infections in hematologic malignancy patients. Semin Respir Infect 2002; 17:99-105.

16. Roling EE, Klepser ME, Wasson A et al: Antifungal activities of fluconazole, caspofungin (MK0991), and anidulafungin (LY 303366) alone and in combination against Candida spp. and Crytococcus neoformans via time-kill methods. Diagn Microbiol Infect Dis 2002; 43:13-17.

17. Zhanel GG, Karlowsky JA, Harding GA et al: In vitro activity of a new semisynthetic echinocandin, LY-303366, against systemic isolates of Candida species, Cryptococcus neoformans, Blastomyces dermatitidis, and Aspergillus species. Antimicrob Agents Chemother 1997; 41:863-865.

18. Zhanel GG, Karlowsky JA, Zelenitsky SA et al: Susceptibilities of Candida species isolated from the lower gastrointestinal tracts of high-risk patients to the new semisynthetic echinocandin LY303366 and other antifungal agents. Antimicrob Agents Chemother 1998; 42:2446-2448.

Original publication:  12/2002

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