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Lipid Amphotericin B Formulations and the Echinocandins. Russell E. Lewis, Pharm.D. Assistant Professor. AMB-D. Is the AMB-deoxycholate Era Over ?. AMB-D. AMB-D. AMB-D. Imidazoles Fluconazole Lipid-AMB Echinocandins/ Itraconazole New Triazoles.

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Lipid Amphotericin B Formulations and the Echinocandins

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Lipid amphotericin b formulations and the echinocandins l.jpg

Lipid Amphotericin B Formulations and the Echinocandins

Russell E. Lewis, Pharm.D.

Assistant Professor


Is the amb deoxycholate era over l.jpg

AMB-D

Is the AMB-deoxycholate Era Over ?

AMB-D

AMB-D

AMB-D

Imidazoles Fluconazole Lipid-AMB Echinocandins/

Itraconazole New Triazoles


Old versus new era of antifungal therapy l.jpg

Amphotericin B-cornerstone

Toxicity a limiting factor

Limited options for prophylaxis or chronic therapy

Limited spectrum of pathogens

Combination therapy often not feasible

Cost

Several treatment options

Improved tolerability and availability of oral formulations

Expanding spectrum of pathogens

Combination therapy-standard of care?

Cost !!!

Old Versus New Era of Antifungal Therapy

Old Era

New Era


Old vs new era of antifungal therapy l.jpg

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

Several treatment options

Improved tolerability and availability of oral formulations

Expanding spectrum of pathogens

Combination therapy-standard of care?

Cost !!!

Old vs. New Era of Antifungal Therapy

Old Era

New Era


Lipid amphotericin b formulations l.jpg

Lipid Amphotericin B Formulations

Abelcet ® ABLC

Amphotec ® ABCD

Ambisome ® L-AMB

Ribbon-like particles

Carrier lipids: DMPC, DMPG

Particle size (µm): 1.6-11

Disk-like particles

Carrier lipids: Cholesteryl sulfate

Particle size (µm): 0.12-0.14

Unilaminarliposome

Carrier lipids: HSPC, DSPG, cholesterol

Particle size (µm) : 0.08

DMPC-Dimyristoyl phospitidylcholine

DMPG- Dimyristoyl phospitidylcglycerol

HSPC-Hydrogenated soy phosphatidylcholine

DSPG-Distearoyl phosphitidylcholine


Key biopharmaceutical differences of the amphotericin b formulations l.jpg

Key Biopharmaceutical Differences of the Amphotericin B Formulations

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


Slide7 l.jpg

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

Outcome

Reference Pathogen(s) Agent Response Survival

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


Slide8 l.jpg

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

Toxicity

Reference Pathogen(s) Agent Infusion Renal

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


Comparison of lipid amb formulations as empiric therapy for febrile neutropenia l.jpg

Comparison of Lipid AMB Formulations as Empiric Therapy for Febrile Neutropenia

Outcome

Toxicity

Reference Agent Response Survival Infusion Renal Comments

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


Lipid amb formulations summary l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

mannoproteins

b1,3

b1,6

glucans

PPL bilayer

b1,3 glucan

synthase

chitin

ergosterol

The Fungal Cell Wall


The echinocandins l.jpg

Cyclic lipopeptides that non-competitively inhibit of 1,3 -b-D glucan synthase

210 kDa integral membrane heterodimeric protein

? Responsible for export of glucan polymer

Three echinocandins

Cancidas ® (caspofungin)

Micafungin (FK463)

Anidulafungin (VER 002)

HO

OH

H

H

O

H

NH

HO

H

NH

H

O

N

H

NH

HO

O

H

H

C

O

H

3

H

H

CH

O

OH

NH

3

N

O

OH

HO

H

NH

N

H

2

H

H

H

H

O

OH

OH

The Echinocandins

Echinocandin “backbone”


Echinocandins spectrum vs yeast l.jpg

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 l.jpg

Echinocandin Activity vs. Biofilm-Embedded Yeast

Antifungal Killing vs. Biofilm-

Embedded Candida spp.

100

90

FLU

80

AMB

70

CAS

60

% Viability (XTT)

50

40

30

20

10

0

0.5

2

16

Antifungal Conc (mg/mL)

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


Echinocandin treated patients with refractory esophagitis l.jpg

Echinocandin-Treated Patients with Refractory Esophagitis

Before After

Patient #1

Patient #2


Echinocandins spectrum vs moulds l.jpg

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?

AfFks1p (IntF)

Aniline blue

Echinocandins-Spectrum vs. Moulds

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


Echinocandins act at the apical tips of aspergillus hyphae l.jpg

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 l.jpg

Update on the Multi-Center Non-Comparative Study of CAS in Adults with IA: Analysis of 90 Patients

Maertens et al. ICAAC 2002.


Slide21 l.jpg

Caspofungin vs. Amphotericin B Deoxycholate in the Treatment of Invasive Candidiasis in Neutropenic and Non-Neutropenic Patients

Caspofungin 70 mg day #1, then 50 mg QD vs.

AMB-D 0.6-1 mg/kg/q24h

* P < 0.05, secondary analysis

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


Slide22 l.jpg

37

4

33

32

5

25

5

3

28

9

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

Favorable Response

Patient Population

n

%

45

5

40

50

26

42

26

14

39

75

Original 83 patients

Complete response

Partial response

Pulmonary (n=64)

Extrapulmonary (n=19)

Leukaemia (n= 60)

Neutropenia (n=19)

AlloHSCT (n=21)

Refractory (n=71)

Intolerant (n=12)

Maertens et al Clin Infect Dis In press


Slide23 l.jpg

Drug-Related Adverse Experiences*

Occurring in  2% of Patients treated with CAS

Caspofungin 50 mg % (N=69)

2.9

2.9

2.9

2.9

3.2

4.9

Clinical Adverse Experiences

Fever

Phlebitis/Infused vein complications

Nausea

Vomiting

Laboratory Adverse Experiences

Increased eosinophils

Increased urine protein

  • 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)

* Possibly, probably or definitely drug-related


Micafungin vs fluconazole for prophylaxis of ifi in patients undergoing hsct l.jpg

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

1

0.9

0.8

0.7

0.6

Proportion of Patients with Treatment Success

  • Administered until:

  • Day +5 neutrophil recovery

  • Day +42

  • Fungal infection

  • Unacceptable toxicity

  • Death

0.5

Micafungin (N=425)

0.4

Fluconazole (N=457)

0.3

P-Value (2 tailed) = 0.025

0.2

0.1

0

0

10

20

30

40

50

60

70

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

Van Burik et al. ICAAC 2002


Slide25 l.jpg

In Favor of

Fluconazole

In Favor of Micafungin (FK463)

Allogeneic

+3.0

Type of Transplant

Autologous

+9.1

or

Syngeneic

GVHD During Study

+5.3

Present

(graft-versus-host disease)

Absent

+10.8

< 16

+15.9

>

16

+5.4

Age

< 65

+4.9

+27.4

>

65

-30

-25

-20

-15

-10

-5

0

5

10

15

20

25

30

Treatment difference (FK463 -

fluconazole

)

Van Burik et al. ICAAC 2002


Safety related to study drug l.jpg

SafetyRelated to Study Drug

fluconazole

(n=457)

77 (16.8%)

14 (3.1%)

12 (2.6%)

15 (3.3%)

33(7.2%)

micafungin

(n=425)

64 (15.1%)

14 (3.3%)

10 (2.4%)

9 (2.1%)

18(4.2%)

Adverse Events

Bilirubinemia

Nausea

Diarrhea

Discontinued study drug

due to adverse event *

* P=0.058 micafungin compared to fluconazole

Van Burik et al. ICAAC 2002


Hepatic and renal adverse events related to study drug l.jpg

Hepatic and Renal Adverse EventsRelated to Study Drug

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

Van Burik et al. ICAAC 2002


Pharmacology of antifungal combinations l.jpg

Pharmacology of Antifungal Combinations

PharmacokineticPharmacodynamic

  • Drug-specific issues

  • Spectrum

  • Synergy or antagonism

  • Resistance

  • Toxicity

Site-specific issues

- Amount of drug

- Rate of accumulation

- Ratio of concentrations

- Bioactivity at site

Sequential use?…..Timing?

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


Antifungal combinations an opinion l.jpg

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


Slide30 l.jpg

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

Time to failure

  • 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

P=0.08

100

90

80

70

60

Percent Successfully Treated

50

40

FLU + placebo

30

FLU + AMB

20

10

0

0

1

2

3

5

8

10

15

20

25

30

Days after Study Enrollment

Rex et al. ICAAC 2001, Abstr #681a


Slide31 l.jpg

Antifungal Pharmacotherapy

Echinocandins

Triazoles

Amphotericin B

Combinations

Diagnostic Tools


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