Are Echinocandins Equal?

Daniel H. Kett, M.D. Professor of Clinical Medicine University of Miami School of Medicine Department of Veterans Affairs Medical Center Potential Conflicts of Interests

• Research Grants – Agency for Healthcare Research and Quality – Akers Bioscience, Inc. – Pfizer, Inc. • Scientific Advisory Boards – Pfizer, Inc. – Cadence Pharmaceuticals – Kimberly Clark • Consult – Pfizer, Inc.

• Amphotericin B IV, nephrotoxic – AmB deoxycholate (Fungizone) – ABLC (Abelcet) – Liposomal amphotericin B (Ambisome) • Azoles – Fluconazole (Diflucan) PO/IV, hepatotoxic – Voriconazole (Vfend) PO/IV, hepatotoxic, CNS • Echinocandins – Caspofungin (Cancidas) IV – Micafungin (Mycamine) IV – Anidulafungin (Eraxis/Ecalta) IV Are Echinocandins Equal?

• All three echinocandins: • Inhibit fungal growth through a non-competitive inhibition of 1,3-β-D-glucan synthase • Share a similar structural chemical backbone • IDSA and ESCMIS guidelines do not differentiate between the three available echinocandins • The only head to head randomized study in Invasive Candidiasis showed non-inferiority between Caspofungin and Micafungin. Echinocandins

Pharmacodynamics Pharmacokinetics • Concentration- – Loading dose Anidulafungin dependent killing • ANID: 200 mg • Prolonged post- • CASPO: 70 mg antifungal effects • MICA: none • AUC/MIC and required C /MIC predictive max – Dosing is daily via IV indices Caspofungin infusion • Candida pharmaco- • ANID: 100 mg dynamic targets similar among • CASPO: 50 mg echinocandins and • MICA: 50/100 mg Candida sp – Tissue penetration • AUC/MIC target=10-20 • No active drug in Micafungin • Cmax/MIC target = 1-3 urinary tract, CSF, vitreous Micafungin and Liver Tumours

• Micafungin is used in babies, children and adults in the following situations: • To treat invasive candidiasis (a type of fungal infection caused by a yeast-like fungus called Candida). ‘Invasive’ means that the fungus has spread into tissue and blood vessels • To prevent infection with Candida in patients who are having a bone marrow transplant or who are expected to have neutropenia (low levels of neutrophils, a type of white blood cell) for 10 days or more. • Mycamine is also used to treat candidiasis in the oesophagus (gullet) in patients over 16 years of age for whom intravenous treatment is suitable. Because of a possible risk of liver tumours, Mycamine is only to be used if other antifungal medicines are not appropriate. Anidulafungin: Dosage and Administration • Original Formulation: Reconstitution with companion diluent – 20% (w/w) Dehydrated Alcohol in Water for Injection

• New USA and European formulation: 100mg lyophilized vial (stored at 5o C) – Reconstitute with 30 mL SWFI – Further dilute with 100 mL of either D5W or NS – Total volume approximately 130 mL – To be administered over 1.5 hrs (at a rate not exceeding 1.1 mg/min) – Reconstituted solution stable for 1 hr under refrigeration – (2-8 degrees C) – Diluted solution stable for up to 24 hrs under refrigeration – (2-8 degrees C) and must be used within 24 hrs.

Are Echinocandins Clinically Equivalent?

• Activity of the three echinocadins against Candida spp. – MICs – Paradoxical growth – Activity against biofilms • Pharmacology – Pharmacokinteics – Drug-drug interactions • Aspergillus activity

• My assessment: – The differences between the echinocandins are real – How these difference impact patient care and results depends on the population being treated and your clinical practice. Echinocandins Invasive Candidiasis Studies (End Points and Success Rates)

Efficacy Success Rate Overall Study Design End Point (cured + improved) Mortality

Primary: Mora-Duarte Caspofungin vs. favourable response at end of 73% vs. 62% 34% vs. 30% et al, 2002 Amphotericin B IV therapy only (MITT) Primary: 87% vs. 90% Micafungin vs. favourable response at end of Kuse et al, Limposomal therapy (per protocol) 40% vs. 40% 2007 Amphotericin B MITT 69% vs. 74% Primary: Pappas et al, Micafungin (100,150 mg) 29% vs. 33% favourable response at end of 76% vs.71% vs. 72% 2007 vs. Caspofungin vs. 26% IV therapy (MITT) Primary: Reboli et al, Anidulafugin vs. favourable response at end of 76% vs. 60%* 23% vs. 33% 2007 Fluconazole IV therapy (MITT)

* (p < 0.05) Defining Success

• Clinical Success – Favorable clinical response: • Complete resolution of signs and symptoms attributable to the invasive mycoses – Favorable microbiological response: • Eradication from follow-up cultures (“presumptive eradication” permitted for non-blood cases if there was no apparent evidence of residual infection from symptoms, physical exam, or radiographic studies) • Mortality – Secondary endpoint Micafungin vs. Caspofungin: Invasive Candidiasis

595 patients In the 100 Mica 100 MITT population: 76.4 Mica 150 80 71.4 72.3 Caspo 70/50 191 pts micafungin 100 mg 199 pts micafungin 150 mg 60

188 pts caspofungin 70/50 mg. 40 33.2 29.0 26.4 10 days of intravenous therapy was required. 20

0 Treatment Success Mortality

Pappas PG, et al. Clin Infect Dis. 2007; 45:883-893. Antifungal Susceptibility of 2,000 Bloodstream Candida isolates in the United States

MIC90 (in µg/mL), by antifungal agent No. of Candida species isolates FLU VOR AFG CFG MFG C. albicans 733 2 0.06 0.03 0.5 0.03 C. glabrata 458 32 1 0.13 1 0.06 C. parapsilosis 391 2 0.06 2 2 2 C. tropicalis 307 16 2 0.13 1 0.06 C. krusei 50 >64 1 0.13 2 0.25 C. lusitaniae 20 2 0.06 0.25 2 2 C. dubliniensis 19 0.5 0.03 0.06 0.5 0.03 C. guilliermondii 9 4 0.06 1 1 0.5

Ostrosky-Zeichner L, et al. Antimicrob Agents Chemother 2003; 47:3149–54 Antifungal Susceptibility of 5346 Invasive Isolates of Candida: Six Years of Global Surveillance

No. of Cumulative % of isolates susceptible at a MIC (μg/ml) ofa: Organism Agent isolates 0.007 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 ≥8 Albicans 2,869 ANID 6.2 33.5 69.5 92.4 99.1 99.5 99.5 99.6 100.0 CASPO 1.7 26.7 74.2 97.1 99.3 99.9 100.0 MICA 11.9 80.6 96.4 99.3 99.4 99.5 99.6 100.0 Parapsilosis 759 ANID 0.3 0.3 0.3 1.4 4.7 27.9 92.5 100.0 CASPO 0.1 0.5 3.3 10.7 52.2 89.5 98.6 99.9 100.0 MICA 0.1 0.3 0.3 0.5 6.1 24.4 79.3 100.0 Glabrata 747 ANID 0.4 7.8 62.4 93.6 99.4 99.7 99.9 99.9 100.0 CASPO 7.0 65.2 95.3 98.4 99.2 99.7 99.9 99.9 99.9 100.0 MICA 13.7 91.4 97.9 98.9 99.5 99.9 99.9 100.0 Tropicalis 625 ANID 3.2 24.2 75.7 95.0 98.4 99.4 99.5 99.5 100.0 CASPO 1.3 31.0 79.7 97.3 99.0 99.7 99.7 99.8 99.8 99.8 100.0 MICA 4.0 39.5 77.6 96.3 98.6 99.5 99.7 100.0 Krusei 136 ANID 2.9 47.1 90.4 99.3 99.3 100.0 CASPO 0.7 0.7 41.9 75.7 94.9 99.3 100.0 MICA 2.2 13.2 85.3 96.3 100.0 Guilliermondii 61 ANID 3.3 6.6 13.1 57.4 90.2 100.0 CASPO 1.6 4.9 11.5 39.3 80.3 95.1 95.1 95.1 100.0 MICA 3.3 3.3 6.6 11.5 21.3 65.6 98.4 100.0 Lusitaniae 58 ANID 1.7 13.8 43.1 96.6 100.0 CASPO 3.4 6.9 44.8 89.7 96.6 100.0 MICA 1.7 8.6 63.8 96.6 98.3 100.0 Pfaller MA et al. J. Clin. Microbiol. 2008; 46:150-156 Candida Bloodstream Infections: SENTRY Antimicrobial Surveillance Program: 2008-2009

Percent Resistant Species ANID CASP MICA FLUC VORI

C. albicans ICU 0.3% 0.3% 0.3% 0.0 0.0 (n=393) non-ICU 0.0 0.2% 0.0 0.0 0.0

C. glabrata ICU 2.2% 2.2% 2.2% 5.9% 5.9% (n=136) non-ICU 3.4% 3.4% 1.7% 6.3% 2.3%

C. parapsilosis ICU 0.0 0.0 0.0 6.8% 0.0 (n=118) non-ICU 0.0 0.0 0.0 4.3% 0.0

C. tropicalis ICU 0.0 0.0 0.0 4.9% 0.0 (n=82) non-ICU 0.0 0.0 0.0 2.2% 1.1%

C. krusei ICU 0.0 6.3% 0.0 N/A 0.0 (n=16) non-ICU 0.0 5.0% 0.0 N/A 0.0

Pfaller MA , et al . Int J Antimicrob Agents. 2011; 38:65-69 Paradoxical Growth Effects of the Echinocandins: Eagle Effect

• Eagle effect or paradoxical growth effect: When Candida spp. are grown in media containing high concentrations of antifungal agents, the result can be a reduced activity of these agents against certain organisms. • Species related and echinocandin specific

Candida species Paradoxical efffect (%) Drug Paradoxical efffect (%) (no. of isolates) CASPO MICA ANID ANID None of the isolates C. albicans (20) 60 0 40 C. dubliniensis isolates (90%) CASPO C. parapsilosis (10) 90 0 0 C. albicans isolates (14%) C. tropicalis (10) 40 70 20 MICA C. dubliniensis isolates (63%) C. krusei (10) 10 60 0 C. glabrata (10) 0 0 0

Chamolis G, et al. Antimicrob Agents Chemother. 2007. Fleischhacker M, et al. Eur J Clin Microbiol 51:2257-2259 Infect Dis. 2008. 27:127-131 Catheters and Biofilms

• Lines and foreign bodies – Remove if possible - better outcomes – Biofilms are important • Fluconazole and voriconazole were ineffective against biofilms of all five L-AMB and Echinocandins Candida species, with none of the isolates showing an azole SMIC of <128 μg/ml. • Echinocandins and Amphotericin much better penetration

FLUC Anaissie et al. Am J Med. 1998;104:238-245. Cole et al. Clin Infect Dis. 1996;22(suppl 2):S73-S88. Nucci et al. Clin Infect Dis. 2002;34:591-599. Schinabeck et al. Antimicrob Agents Chemother. 2004;48:1727-1732. Fiori B, et al. Antimicrob Agents Chemother. 2011 Mar 21. [Epub ahead of print] Activity of anidulafungin and other antifungal agents against biofilms formed by Candida species

Species (no. of Type of No. of isolates at MIC (μg/ml) Drug isolates) MIC ≤0.03 0.06 0.125 0.25 0.5 1 2 4 8 16 >16

C. albicans (20) Biofilm 2 14 4

C. parapsilosis (40) Biofilm 2 9 11 14 4

Anidulafungin C. tropicalis (20) Biofilm 1 17 2

C. glabrata (20) Biofilm 14 4 2

C. krusei (20) Biofilm 2 7 9 2

C. albicans (20) Biofilm 2 10 5 3

C. parapsilosis (40) Biofilm 1 9 15 8 4 3

Caspofungin C. tropicalis (20) Biofilm 5 11 4

C. glabrata (20) Biofilm 2 4 9 5

C. krusei (20) Biofilm 4 7 7 2

Fiori B, et al. Antimicrob Agents Chemother. 2011. 55(6):3031-5 Anidulafungin Undergoes Spontaneous Chemical Degradation at Physiologic Conditions

Inactive Peptide Converted to Chain breaks at Physiologic Active Molecule Peptidic Degradants 37°C and pH 7.4 and Eliminated in Feces

 Anidulafungin is the only echinocandin not hepatically metabolized or renally excreted  Because anidulafungin elimination is not dependent on hepatic/renal function  There are no known drug interactions of clinical significance  There are no required dose adjustments 18 Anidulafungin Clearance differs from other echinocandins

Intravenous only

OATP-1B1

Caspofungin N-acetylation

Micafungin COMT

degradation Slow chemical chemical Slow Anidulafungin Biliary elimination

OATP=Organic anion-transporting polypeptide. Micafungin is metabolized by arylsulfatase and secondarily by COMT (catechol-O-methyltransferase). Anidulafungin Has Simple Linear PK

120

100

80

h/L) 

(mg 60



40 AUC

20

0 0 50 100 150 Anidulafungin Dose (mg)

20 Metabolism and Interaction Profile of the Available Echinocandins

Caspofungin Micafungin Anidulafungin

Yes Hepatic Yes (Arylsulfatase and catechol-O- No Metabolism? (N-acetylation) methyltransferase; some CYP3A hydroxylation)

CYP3A4 Inhibitor? No Weak No

Cyclosporine; Tacrolimus Drug Rifampin; Efavirenz; Nevirapine; Sirolimus No known interactions Interactions? Phenytoin; Dexamethasone; Nifedipine Carbamazepine

Yes Dose Moderate hepatic dysfunction No No Adjustments? With CYP inducers

21 Half-life of the Available Echinocandins

Beta Half-life (Hours)

26.5

14-17

9-11

Anidulafungin Micafungin Caspofungin

Comparisons do not imply interchangeability or comparable efficacy and safety. Eraxis [package insert]. New York, NY: Pfizer Inc; 2007. Mycamine for Injection [package insert]. Tokyo, Japan: Astellas Pharma, Inc; 2006. Cancidas for Injection [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2005. Stone JA et al. Antimicrob Agents Chemother. 2002;46:739-745. 22 Volume of Distribution of the Echinocandins

Vd (L)

30-50 L (Typical Value 33.2 L) 27 L (0.39 L/kg in a 70- kg Adult)

8-10 L

Anidulafungin Micafungin Caspofungin

Comparisons do not imply interchangeability or comparable efficacy and safety. Eraxis [package insert]. New York, NY: Pfizer Inc; 2007. Dowell JA et al. J Clin Pharmacol. 2004;44:590-598. Mycamine for Injection [package insert]. Tokyo, Japan: Astellas Pharma, Inc; 2006. Stone JA et al. Antimicrob Agents Chemother. 2004;48:815-823. 23 Distribution Into Tissue: Fischer 344 rats following a single IV bolus 5 mg/kg dose of 14C-anidulafungin

Tissue/Plasma AUC Ratio Organ for Parent Drug*

Liver 12.4

Kidney 10.7

Spleen 9.2

Lung 10.4

 Tissue levels were 9- to 12-fold higher than plasma

*Following a single IV bolus 5 mg/kg dose of 14C-anidulafungin Data on file. Pfizer Inc, New York, NY. 24 Anidulafungin PK Unaffected By Compromised Hepatic or Renal Function

Hepatic Impairment Renal Impairment*

3.0 3.0 Control (n=8) Control (n=8)

2.5 Mild (n=6) 2.5 Mild (n=6)

Moderate (n=6) Moderate (n=6)

Severe (n=6) Severe (n=6)

g/mL) 2.0 2.0 

1.5 1.5

Anidulafungin Anidulafungin 1.0 1.0 Concentration ( Concentration 0.5 0.5

0 0 0 20 40 60 80 100 120 140 160 0 20 40 60 80 100 120 140 160 Time After Study Drug Administration (H) Time After Study Drug Administration (H)

*Anidulafungin is not dialyzable and may be administered without regard to timing of hemodialysis. Vazquez JA. Clin Ther. 2005;27:657-673. 25 Combination Therapy for Invasive Aspergillosis • Prospective, randomized, double- blind trial in allo-HSCT recipients and patients with haematological malignancies with proven or probable IA • Patients were randomized 1:1 to receive either voriconazole (monotherapy) or voriconazole plus anidulafungin (combination therapy). • Combination therapy for 2–4 weeks; after 2 weeks, the investigator could switch to voriconazole monotherapy, to complete at least 6 weeks of antifungal treatment. Marr KA, et al. abstract LB 2812 ECCMID 2011 Conclusions: Are Echinocandins Equal?

• The differences between the echinocandins are real – Dosing – Pharmacokinetics and Pharmacodynamics – MICs and resistance – Tissue penetration – Drug interactions

• Don’t expect a sufficiently large randomized trial comparing agents to demonstrate differences • How these difference impact patient care depends on your clinical practice and the population being treated.