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Lipid Amphotericin B Formulations and the Echinocandins

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

  2. AMB-D Is the AMB-deoxycholate Era Over ? AMB-D AMB-D 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 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

  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 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

  5. 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

  6. Key Biopharmaceutical Differences of the Amphotericin B Formulations Groll, Piscetelli and Walsh Adv. Pharmacol 1998;44:343-500.

  7. 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

  8. 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

  9. 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

  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. mannoproteins b1,3 b1,6 glucans PPL bilayer b1,3 glucan synthase chitin ergosterol The Fungal Cell Wall

  14. 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”

  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 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

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

  18. 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

  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 Maertens et al. ICAAC 2002.

  21. 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.

  22. 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

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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

  28. 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

  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 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

  31. Antifungal Pharmacotherapy Echinocandins Triazoles Amphotericin B Combinations Diagnostic Tools

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