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Lipid Amphotericin B Formulations and the Echinocandins Russell E. Lewis, Pharm.D. Assistant Professor.

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Presentation on theme: "Lipid Amphotericin B Formulations and the Echinocandins Russell E. Lewis, Pharm.D. Assistant Professor."— Presentation transcript:

1 Lipid Amphotericin B Formulations and the Echinocandins Russell E. Lewis, Pharm.D. Assistant Professor

2 Is the AMB-deoxycholate Era Over ? AMB-D Imidazoles Fluconazole Lipid-AMB Echinocandins/ Itraconazole New Triazoles

3 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 EraNew Era

4 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 EraNew Era

5 Lipid Amphotericin B Formulations Ribbon-like particles Carrier lipids: DMPC, DMPG Particle size : 1.6-11 Particle size (µm): 1.6-11 Abelcet ® ABLC Amphotec ® ABCD Ambisome ® L-AMB Disk-like particles Carrier lipids: Cholesteryl sulfate Particle size : 0.12-0.14 Particle size (µm): 0.12-0.14 Unilaminar liposome Carrier lipids: HSPC, DSPG, cholesterol Particle size : 0.08 Particle size (µm) : 0.08 DMPC-Dimyristoyl phospitidylcholine DMPG- Dimyristoyl phospitidylcglycerol HSPC-Hydrogenated soy phosphatidylcholine DSPG-Distearoyl phosphitidylcholine

6 Key Biopharmaceutical Differences of the Amphotericin B Formulations AmB-d Fungizone ® L-AmB AmBisome ® ABLC Abelcet ® ABCD Amphotec ® Mol% AmB34%10%35%50% Lipid Config.MicellesSUVsRibbon-likeDisk like Diameter (µm)< 0.40.081.6-11.00.12-0.14 Dosage0.5-1 mg/kg3-5 mg/kg5 mg/kg3-4 mg/kg Cmax (vs. AmB-d) -IncreasedDecreased AUC (vs. AmB-d) -IncreasedDecreased Vd (vs. AmB-d) -DecreasedSimilarIncreased Cl (vs. AmB-d) -DecreasedIncreasedSimilar Nephrotox.+++ + + + Infusion Tox.HighMildModerate Groll, Piscetelli and Walsh Adv. Pharmacol 1998;44:343-500.

7 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 MixedL-AMBSame Leenders 1997 Cryptococcus spp.L-AMBSame Anaisse 1995 Candida spp.ABLCSame Bowden 2002 Aspergillus spp.ABCDSame Hamill 1999 Cryptococcus spp.L-AMBSame Johnson 2002 H. capsulatumL-AMBGreater Outcome

8 Reference Pathogen(s) Agent Infusion Renal Wingard. Clin Infect Dis 2002; 35:891-5 Leenders 1998 MixedL-AMBLower Leenders 1997 Cryptococcus spp.L-AMBLower Anaisse 1995 Candida spp.ABLCSameLower Bowden 2002 Aspergillus spp.ABCDGreaterLower Hamill 1999 Cryptococcus spp.L-AMBLower Johnson 2002 H. capsulatumL-AMBLower Toxicity Lipid AMB formulations vs. Conventional AMB When Used as First-Line Therapy In Prospective Randomized Trials

9 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 Lower L-AMB Lower L-AMB L-AMB 1-3 mg/kg/day White 1998 ABCD vs. AMB-D Similar Higher ABCD Lower ABCD Infusion-related hypoxia > ABCD Walsh 1999 L-AMB vs. AMB-D Similar Lower L-AMB Lower L-AMB Fewer breakthrough infection in L-AMB Wingard 2000 L-AMB vs. ABLC Similar Greater for ABLC Primary endpoint- safety Fleming 2001 ABLC vs. Ambisome 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

10 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

11 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

12 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

13 The Fungal Cell Wall

14 The Echinocandins 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)

15 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.

16 Echinocandin Activity vs. Biofilm- Embedded Yeast 0 10 20 30 40 50 60 70 80 90 100 0.5216 FLU AMB CAS % Viability (XTT) Antifungal Conc ( g/mL) Ramage et al. Antimicrob Agent Chemother 2002;46:3634 Antifungal Killing vs. Biofilm- Embedded Candida spp.

17 Echinocandin-Treated Patients with Refractory Esophagitis Before After Patient #1 Patient #2

18 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;183:2273-79

19 Echinocandins Act at the Apical Tips of Aspergillus Hyphae DiBAC Bowman et al. Antimicrob Agent Chemother 2002;46:3001-12

20 Update on the Multi-Center Non-Comparative Study of CAS in Adults with IA: Analysis of 90 Patients PulmonaryDisseminatedSingle Organ N of Pts.64136 Favorable (CR/PR) 32 (50%)3 (23%)2 (33%) Maertens et al. ICAAC 2002.

21 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 MITT71/115 (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.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

22 37 4 33 32 5 25 5 3 28 9 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) Patient Population Efficacy and safety of caspofungin in invasive aspergillosis in patients refractory to or intolerant of other therapy 45 5 40 50 26 42 26 14 39 75 n % Favorable Response Maertens et al Clin Infect Dis In press

23 Caspofungin 50 mg % (N=69) 2.9 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 Vomiting Laboratory 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

24 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 010203040506070 Micafungin (N=425) Fluconazole (N=457) Time to Treatment Failure (Days Since First Dose of Study Drug) Proportion of Patients with Treatment Success 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

25 -30-25-20-15-10-5051015202530 +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 Transplant Allogeneic Autologous orSyngeneic Present Absent < 16 > 16 < 65 > 65 Treatment difference (FK463 -fluconazole ) GVHD During Study (graft-versus-host disease) Age Van Burik et al. ICAAC 2002

26 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 drug due to adverse event * * P=0.058 micafungin compared to fluconazole Safety Related to Study Drug Van Burik et al. ICAAC 2002

27 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%) 4 (0.9%) 8 (1.8%) LFTs abnormal SGOT / AST SGPT / ALT Serum Cr Hypokalemia Hepatic and Renal Adverse Events Related to Study Drug Van Burik et al. ICAAC 2002

28 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?

29 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

30 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 0123581015202530 FLU + placebo FLU + AMB Days after Study Enrollment P=0.08 Time to failure Rex et al. ICAAC 2001, Abstr #681a Percent Successfully Treated

31 Amphotericin B Triazoles Echinocandins Combinations Diagnostic Tools Antifungal Pharmacotherapy


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