Presentation on theme: "Lipid Amphotericin B Formulations and the Echinocandins Russell E. Lewis, Pharm.D. Assistant Professor."— Presentation transcript:
Lipid Amphotericin B Formulations and the Echinocandins Russell E. Lewis, Pharm.D. Assistant Professor
Is the AMB-deoxycholate Era Over ? AMB-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 EraNew 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 EraNew Era
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 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)
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 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.
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;183:2273-79
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 PulmonaryDisseminatedSingle Organ N of Pts.64136 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 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
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
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
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
-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
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
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
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 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
Amphotericin B Triazoles Echinocandins Combinations Diagnostic Tools Antifungal Pharmacotherapy