lipid amphotericin b formulations and the echinocandins russell e. lewis, pharm.d. assistant...
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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
s
Co
mb
inat
ion
s
Diagnostic Tools
Antifungal Pharmacotherapy