Lipid Amphotericin B Formulations and the Echinocandins

Russell E. Lewis, Pharm.D.

Assistant Professor

Is the AMB-deoxycholate Era Over ?

AMB-D

AMB-D

AMB-DAMB-D

Imidazoles Fluconazole Lipid-AMB Echinocandins/ Itraconazole New Triazoles

• Amphotericin B-cornerstone• Toxicity a limiting factor• Limited options for

prophylaxis or chronic therapy

• Limited spectrum of pathogens

• Combination therapy often not feasible

• Cost

Old Versus New Era of Antifungal Therapy

• Several treatment options

• Improved tolerability and availability of oral formulations

• Expanding spectrum of pathogens

• Combination therapy-standard of care?

• Cost !!!

Old Era New Era

• Limited to amphotericin B• Toxicity a limiting factor• Limited options for

prophylaxis or chronic therapy

• Limited spectrum of pathogens

• Combination therapy often not feasible

• Cost less of a factor

Old vs. New Era of Antifungal Therapy

• Several treatment options

• Improved tolerability and availability of oral formulations

• Expanding spectrum of pathogens

• Combination therapy-standard of care?

• Cost !!!

Old Era New Era

Lipid Amphotericin B Formulations

Ribbon-like particlesRibbon-like particlesCarrier lipids: DMPC, Carrier lipids: DMPC, DMPGDMPGParticle size Particle size (µm): 1.6-11 : 1.6-11

Abelcet Abelcet ®® ABLC ABLC Amphotec Amphotec ®® ABCD ABCD Ambisome Ambisome ®® L-AMB L-AMB

Disk-like particlesDisk-like particlesCarrier lipids: Cholesteryl Carrier lipids: Cholesteryl sulfatesulfateParticle size Particle size (µm): 0.12-0.14 : 0.12-0.14

UnilaminarUnilaminar liposomeliposomeCarrier lipids: HSPC, DSPG, Carrier lipids: HSPC, DSPG, cholesterolcholesterolParticle size Particle size (µm) : 0.08 : 0.08

DMPC-Dimyristoyl phospitidylcholineDMPG- Dimyristoyl phospitidylcglycerol

HSPC-Hydrogenated soy phosphatidylcholineDSPG-Distearoyl phosphitidylcholine

Key Biopharmaceutical Differences of the Amphotericin B Formulations

AmB-d

Fungizone®

L-AmB

AmBisome®

ABLC

Abelcet®

ABCD

Amphotec®

Mol% AmB 34% 10% 35% 50%

Lipid Config. Micelles SUVs Ribbon-like Disk like

Diameter (µm) < 0.4 0.08 1.6-11.0 0.12-0.14

Dosage 0.5-1 mg/kg 3-5 mg/kg 5 mg/kg 3-4 mg/kg

Cmax (vs. AmB-d) - Increased Decreased Decreased

AUC (vs. AmB-d) - Increased Decreased Decreased

Vd (vs. AmB-d) - Decreased Similar Increased

Cl (vs. AmB-d) - Decreased Increased Similar

Nephrotox. +++ + + +

Infusion Tox. High Mild Moderate Moderate

Groll, Piscetelli and Walsh Adv. Pharmacol 1998;44:343-500.

Reference Pathogen(s) Agent Response Survival

Lipid AMB formulations vs. Conventional AMB When Used as First-Line Therapy In Prospective Randomized Trials

Wingard. Clin Infect Dis 2002; 35:891-5

Leenders 1998

Mixed L-AMB Same Same

Leenders

1997

Cryptococcus spp. L-AMB Same Same

Anaisse

1995

Candida spp. ABLC Same Same

Bowden 2002

Aspergillus spp. ABCD Same Same

Hamill

1999

Cryptococcus spp. L-AMB Same Same

Johnson

2002

H. capsulatum L-AMB Greater Greater

Outcome

Reference Pathogen(s) Agent Infusion Renal

Wingard. Clin Infect Dis 2002; 35:891-5

Leenders 1998

Mixed L-AMB Lower Lower

Leenders

1997

Cryptococcus spp. L-AMB Lower Lower

Anaisse

1995

Candida spp. ABLC Same Lower

Bowden 2002

Aspergillus spp. ABCD Greater Lower

Hamill

1999

Cryptococcus spp. L-AMB Lower Lower

Johnson

2002

H. capsulatum L-AMB Lower Lower

Toxicity

Lipid AMB formulations vs. Conventional AMB When Used as First-Line Therapy In Prospective Randomized Trials

Comparison of Lipid AMB Formulations as Empiric Therapy for Febrile Neutropenia

Wingard. Clin Infect Dis 2002; 35:891-5

Prentice

1997

L-AMB vs.

AMB-D

Similar Similar Lower

L-AMB

Lower

L-AMB

L-AMB 1-3 mg/kg/day

White

1998

ABCD vs.

AMB-D

Similar Similar Higher

ABCD

Lower

ABCD

Infusion-related hypoxia > ABCD

Walsh

1999

L-AMB vs. AMB-D

Similar Similar Lower

L-AMB

Lower

L-AMB

Fewer breakthrough infection in L-AMB

Wingard

2000

L-AMB vs.

ABLC

Similar Similar Greater for ABLC

Greater for ABLC

Primary endpoint-safety

Fleming

2001

ABLC vs.

Ambisome

Similar for fungal

Similar for fungal

Higher

ABLC

Lower for L-AMB

Mild abnormalities in LFT: L-AMB > ABLC

Outcome

Reference Agent Response Survival Infusion Renal Comments

Toxicity

Lipid AMB Formulations-Summary

• Efficacy• Lipid formulation > AMB-deoxy

• Nephrotoxicity• L-AMB < ABLC < ABCD << AMB-deoxy

• Infusion related toxicity• L-AMB < ABLC < ABCD < AMB-deoxy

• Product cost (AWP)• L-AMB > ABLC > ABCD > AMB-deoxy

Continuous Infusion Amphotericin B

• Rationale:• “Simulate” the release of free AMB from the lipid

formulation by using unconventional dosing

• Controversial study (Eriksson et al. BMJ 2001)• 80 febrile neutropenic patients randomized to

• 0.97 mg/kg CI over 24 hours• 0.97 mg/kg rapid infusion over 4 hours

• CI group had fewer side effects and less nephrotoxicity, mortality was higher in rapid infusion group.

• Similar results recently reported for 2 mg/kg/day!

Eriksson et al. BMJ 2001;322:579-582

Unanswered Questions Concerning Lipid Formulations

• Optimal dosing

• Bioactivity in respective tissue compartments

• Use in established but reversible acute renal failure

• Prophylaxis/Aerosolization

• Long-term toxicities

• Cost-effective use in lower risk patients

The Fungal Cell Wall

1,6glucans

1,3

PPL bilayer

chitin

ergosterol

1,3 glucansynthase

mannoproteins

The Echinocandins

OH

H H

HO

OH

H NH

O

NHH

HO

H2N

HO O

NH

H3C

HO H

H

O

NH

H

HO OH

H

H NH

NH

O

CH3

OH

H

HO

N

OH

OH

H

Echinocandin “backbone” • Cyclic lipopeptides that non-competitively inhibit of 1,3 -D glucan synthase• 210 kDa integral membrane

heterodimeric protein

• ? Responsible for export of glucan polymer

• Three echinocandins• Cancidas ® (caspofungin)

• Micafungin (FK463)

• Anidulafungin (VER 002)

Echinocandins-Spectrum vs. Yeast

• Fungicidal vs. Candida spp. including many fluconazole-resistant species• C. albicans = C. tropicalis = C.

glabrata = C. krusei < C. parapsilosis = C. lusitaniae

• No activity against C. neoformans

Kuhn et al. Antimicrob Agent Chemother 2002;46:1773-80.

Echinocandin Activity vs. Biofilm-Embedded Yeast

0102030405060708090

100

0.5 2 16

FLUAMBCAS

% V

iabi

lity

(XT

T)

Antifungal Conc (g/mL)

Ramage et al. Antimicrob Agent Chemother 2002;46:3634

Antifungal Killing vs. Biofilm-Embedded Candida spp.

Echinocandin-Treated Patients with Refractory Esophagitis

Before After

Patient #1

Patient #2

Echinocandins-Spectrum vs. Moulds

AfFks1p (IntF)

Aniline blue

• Active against Aspergillus species• Glucan synthase localized in

apical tips

• Activity against other yeast and moulds is less well described or variable• Mycelial forms of endemic

mycoses?

Beauvais et al. J. Bacteriol 2001;183:2273-79Beauvais et al. J. Bacteriol 2001;183:2273-79

Echinocandins Act at the Apical Tips of Aspergillus Hyphae

DiBAC

Bowman et al. Antimicrob Agent Chemother 2002;46:3001-12

Update on the Multi-Center Non-Comparative Study of CAS in Adults with IA: Analysis

of 90 Patients

Pulmonary Disseminated Single Organ

N of Pts. 64 13 6

Favorable (CR/PR)

32 (50%) 3 (23%) 2 (33%)

Maertens et al. ICAAC 2002.

Caspofungin vs. Amphotericin B Deoxycholate in the Treatment of Invasive Candidiasis in

Neutropenic and Non-Neutropenic Patients

CAS[95% CI]

AMB[95% CI]

Difference adjusted for stratification

MITT 71/115 (74%)[65-82]

71/115 (62%)[53-71]

12.7%[-0.7-26]

End of Therapy response *

71/88 (81%)[72-89]

63/97 (65%)[55-75]

15.4%[1.1-29.7]

Mora-Duarte et al. Volume 348:1287-1288 March 27, 2003.

* P < 0.05, secondary analysis

Caspofungin 70 mg day #1, then 50 mg QD vs.AMB-D 0.6-1 mg/kg/q24h

37 43332 525 5 328 9

Original 83 patients Complete response Partial responsePulmonary (n=64)Extrapulmonary (n=19)Leukaemia (n= 60) Neutropenia (n=19) AlloHSCT (n=21)Refractory (n=71) Intolerant (n=12)

Patient Population

Efficacy and safety of caspofungin in invasive aspergillosis in patients refractory to or intolerant

of other therapy

45 54050264226143975

n %

Favorable Response

Maertens et al Clin Infect Dis In press

Caspofungin 50 mg % (N=69)

2.92.92.92.9

3.2 4.9

• Few significant drug interactions– P450 Inducers (increase CAS dose to 70 mg day)– Tacrolimus (monitor levels and adjust dose)– Cyclosporin A (avoid or closely monitor LFTs)

Clinical Adverse Experiences Fever Phlebitis/Infused vein complications Nausea VomitingLaboratory Adverse Experiences Increased eosinophils Increased urine protein

Drug-Related Adverse Experiences* Occurring in 2% of Patients treated with CAS

* Possibly, probably or definitely drug-related

Micafungin vs. Fluconazole for Prophylaxis of IFI in Patients Undergoing HSCT

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 10 20 30 40 50 60 70

Micafungin (N=425)Fluconazole (N=457)

Time to Treatment Failure (Days Since First Dose of Study Drug)

Pro

po

rtio

n o

f P

ati

ents

wit

h

Tre

atm

en

t S

uc

ces

s

P-Value (2 tailed) = 0.025

Van Burik et al. ICAAC 2002

Administered until:-Day +5 neutrophil recovery-Day +42-Fungal infection-Unacceptable toxicity-Death

-30 -25 -20 -15 -10 -5 0 5 10 15 20 25 30

+3.0

+9.1

+5.3

+10.8

+15.9

+5.4

+4.9

+27.4

In Favor of Micafungin (FK463)In Favor of Fluconazole

Type of TransplantAllogeneic

Autologousor Syngeneic

Present

Absent

< 16

> 16

< 65

> 65

Treatment difference (FK463 - fluconazole )

GVHD During Study(graft-versus-host disease)

Age

Van Burik et al. ICAAC 2002

micafungin(n=425)

64 (15.1%)

14 (3.3%)

10 (2.4%)

9 (2.1%)

18 (4.2%)

fluconazole(n=457)

77 (16.8%)

14 (3.1%)

12 (2.6%)

15 (3.3%)

33 (7.2%)

Adverse Events

Bilirubinemia

Nausea

Diarrhea

Discontinued study drugdue to adverse event *

* P=0.058 micafungin compared to fluconazole

SafetyRelated to Study Drug

Van Burik et al. ICAAC 2002

micafungin(n=425)

4 (0.9%)

3 (0.7%)

4 (0.9%)

1 (0.2%)

8 (1.9%)

fluconazole(n=457)

10 (2.2%)

9 (2%)

9 (2%)

4 (0.9%)

8 (1.8%)

LFTs abnormal

SGOT / AST

SGPT / ALT

Serum Cr

Hypokalemia

Hepatic and Renal Adverse EventsRelated to Study Drug

Van Burik et al. ICAAC 2002

Pharmacology of Antifungal Combinations

Pharmacokinetic Pharmacodynamic

Site-specific issues - Amount of drug - Rate of accumulation - Ratio of concentrations - Bioactivity at site

Drug-specific issues- Spectrum- Synergy or antagonism- Resistance- Toxicity

Lewis and Kontoyiannis. Pharmacotherapy 2001;21:49S-164S

Sequential use?…..Timing?

Antifungal combinations…an opinion

• Pharmacokinetic • Beneficial:

• AMB + 5-FC• AMB + FLU• Echinocandin + newer triazole • L-AMB + AMB-Dx1?

• Pharmacodynamic (from animal studies)• Beneficial:

• AMB + 5-FC• AMB/L-AMB + CAS• Echinocandin + newer triazole

High-Dose Fluconazole Plus Placebo vs. Fluconazole plus Amphotericin B for Candidemia in Non-Neutropenic

Patients

• FLU 800 mg/d vs. AMB 0.7 mg/kg + FLU 800 mg/d

• N=219• Higher APACHE II in FLU

monotherapy arm

• Success rates:• F + P = 56%• F + A = 69%• Fungemia persisted longer in

F + P arm (P = 0.02)

• Nephrotoxicity more common in AMB + FLU

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 5 8 10 15 20 25 30

FLU + placebo

FLU + AMB

Days after Study Enrollment

P=0.08

Time to failure

Rex et al. ICAAC 2001, Abstr #681a

Per

cen

t S

ucce

ssfu

lly T

reat

ed

Am

ph

ote

rici

n B

Tri

azo

les

Ech

ino

can

din

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Co

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inat

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Diagnostic Tools

Antifungal Pharmacotherapy