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Are We Under-Dosing Antifungal Therapy?

Are We Under-Dosing Antifungal Therapy?. Lessons learned from mice and men . Russell E. Lewis, Pharm.D., FCCP Associate Professor. Micafungin Anidulafungin Posaconazole. “All drugs known to humans are poisons, only the amount or dose determine the effects.” Paracelsus, 1490 - 1541.

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Are We Under-Dosing Antifungal Therapy?

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  1. Are We Under-Dosing Antifungal Therapy? Lessons learned from mice and men Russell E. Lewis, Pharm.D., FCCP Associate Professor

  2. Micafungin Anidulafungin Posaconazole “All drugs known to humans are poisons, only the amount or dose determine the effects.” Paracelsus, 1490 - 1541. Caspofungin Voriconazole ABCD L-AmB ABLC Terbinafine Griseofulvin Amphotericin B Itraconazole Ketoconazole Fluconazole Nystatin Miconazole 5-FC Antifungal Therapy:The Last 50 Years # of drugs 18 16 14 12 10 8 6 4 2 0 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 2006 Year Slide concept: John Rex, M.D.

  3. Characteristics of Drugs That Are Good Candidates for Dosage Escalation Safety Predictable pharmacokinetics Concentration-dependent pharmacodynamics

  4. Dosage-Fractionalized Study Design 35 Q8h Q12h Q24h 30 Same AUC 25 20 Serum (µg/mL) 15 10 5 MIC (µg/mL) 0 0.5 8 12 16 20 24.5 32 36 40 44 Pharmacokinetic/Pharmacodynamic Profiles Time >MIC (time-dependent killing) AUC24 /MIC or Peak/MIC (concentration-dependent killing) MIC MIC D Andes. Antimicrob Agent Chemother 2003;47:1179

  5. Safety, Plasma Concentrations and Efficacy of High-Dose Fluconazole in Invasive Mould Infections All pts were receiving 2000 mg/day Mean CPss (µg/mL) % Experiencing AE Fluconazole Daily Dose Linear, predictable PK Favorable safety at Candida dosages Concentration-dependent PK? Anaissie et al. J Infect Dis 1995;172:599-602.

  6. AUC/MIC 25-50 Relationship Between Fluconazole 24 h AUC/MIC and Outcome Against C. albicans with Varying MICs K-1 MIC 0.5 mg/l 98-17 MIC 16.0 mg/l 7 98-234 MIC 32.0 mg/l 6 Log10 CFU/Gram Kidney ED 50 5 1 10 100 1000 10000 24 Hour AUC/MIC Andes Antimicrob Agent Chemother 1999;43:2116

  7. Fluconazole MIC and the Fluconazole Dose/MIC Ratio Correlate with Therapeutic Response among Patients with Candidemia 24- hour MICs 48- hour MICs Dose/MIC > 50 results in > 70% efficacy Clancy et al. Antimicrob Agent Chemother 2005;39:3171.

  8. C H 3 H C 3 N N F l l C C C H 3 N N H C 3 N N N F H O N N O O O H N N N N O N H F F C H 3 O H Posaconazole pKa 3.6 log P-3 Biopharmaceutical Differences inAzole Antifungals Protein Binding N N N O O N N N N N O O N H N Itraconazole pKa 3.7 log P-5.66 N Fluconazole pKa 2 N N F F F Voriconazole pKa 1.63 Lipid solubility

  9. Triazole PK/PD TargetAnimal Model Prediction-Invasive Candidiasis Ravuconazole Protein Binding Fluconazole 9 Voriconazole Itraconazole 99.8% Fluconazole 12% Voriconazole 58% Ravuconazole 98% Posaconazole 98% Posaconazole 8 3 0 0 7 1 0 0 Log CFU10/Kidneys 6 3 0 Free Drug 24-hour AUC/MIC 5 4 1 0 3 3 2 1 0.01 0.1 1 10 100 1000 0 . 0 1 0 . 1 1 1 0 1 0 0 MIC (µg/mL) Total Drug AUC/MIC Andes Infect Dis Clin N Amer 2003;17:635

  10. Efficacy of Posaconazole vs. Itraconazole in the Treatment and Prevention Of Experimental Invasive Aspergillosis Sustained serum levels > 1 µg/mL Petraitiene et al. Antimicrob Agent Chemother 2001;45:857-869.

  11. Posaconazole Absorption in Fasted Subjects 450 800 mg qd 400 400 mg bid 350 200 mg qid 300 250 Posaconazole (ng/mL) 200 150 100 50 0 0 4 8 12 16 20 24 28 32 36 40 44 48 Time (h) Ezzet et al. Clin Pharmacokinet. 2005;44:211-20.

  12. CAP 400 CAP 600 CAP 800 SOL 400 SOL 800 S/C 1200 Variable Exposures and Pharmacokinetics of Itraconazole and Voriconazole in Humans Influence of CYP2C19 Genotype on Average Steady-State Plasma Voriconazole Concentrations Interpatient Variability in Itraconazole Exposures During Oral Prophylaxis Toxicity? Itraconazole trough conc (ng/mL) Efficacy Homozygous Extensive metabolizer (n=108) Heterozygous Extensive metabolizer (n=39) Homozygous Poor metabolizer (n=8) Glasmacher et al. Mycoses 1999;42:443-51. Vfend NDA Submission, www.fda.gov

  13. Hepatic toxicity; Drug interactions; Hypoglycemia; QTc Prolongation Microbiological identification to species level, MIC Drug conc. monitoring; Genotyping? Triazole Dosage Escalation-Summary Some drawbacks can be overcome with laboratory monitoring

  14. H N 2 H O O H O O H O N H O H N H C H 3 H O N H N H N O N H O H C H N O H 3 H N 2 O H H N H C 3 H O N H O H C 3 C H C H 3 3 C H 3 N H H O N O O H H N H O N C H 3 O H O H O H O H O O H H O O H H O N H H O H O H C 3 N H H N 2 H N O H H O N H C H 3 H N H O O H O H O H H O H C 3 O O H O N O H H O H H O anidulafungin O caspofungin O O N O N O O O O N O O O S O O O micafungin

  15. Echinocandins: Ideal Drugs for Dosage Escalation? • Safety: • All three echinocandins are well tolerated up to dosages of >300 mg/day • Predictable PK: • All three drugs exhibit dose-proportional pharmacokinetics…although penetration into some sites may be sub-optimal • Concentration-dependent PD: • All three drugs exhibit concentration-dependent pharmacodynamics in vitro, in animal models, (Cmax:MIC > 4; or AUC:MIC >150), and in Phase II studies

  16. Relationship Between an Aminocandin, HMR 3270, PK/PD Parameters and Efficacy Against C. albicans in a Neutropenic Murine Model 5 2 2 R = 97.8% 2 R = 61.4% R = 79.3% 4 3 Log CFU10/Kidneys 2 1 0 -1 -2 0.3 1 3 10 30 30 100 300 1000 0 20 40 60 80 100 Peak/MIC AUC/MIC Time Above MIC (%) Antimicrob Agent Chemother 2003;47:1187-92.

  17. Alternative Day Dosing of Micafungin in the Treatment of Esophageal Candidiasis Endoscopic Cure Rate Buell et al. ICAAC 2005

  18. 96 hr Survival: 65% 50% 55% 85% 80% 75% 85% 80% 75% p < 0.01 Concentration-Dependent Activity of Caspofungin Against A. fumigatus Log Fungal Burden CE Lower Limit Detection q6 q24 q48 0.25 mg/kg q6 q24 q48 1.0 mg/kg q6 q24 q48 4.0 mg/kg Control Wiederhold et al. J Infect Dis 2004;190:1464-71.

  19. Paradoxical “Eagle Effect” atHigh Echinocandin Dosages • Can be reproducibly detected in vitro, but more variable in vivo models • In vivo: diminished fungal clearing at higher dosages (4-8 mg/kg) that can eventually be overcome at higher dosages • Caspofungin > micafungin, anidulafungin • Mechanisms? • Micelle formation • Transporter/efflux • Activation of homeostatic cell-wall stress response • Yet undefined resistance mechanism? Douglas et al. ICAAC 2005 Wiederhold et al. J Infect Dis 2004;190:1464-71. Wiederhold et al. Antimicrob Agent Chemother 2005;49:5146 Stevens et al. Antimicrob Agent Chemother 2004;48:3407 Stevens et al. Diagn Microbiol Infect Dis 2005;51:173-8 Clemons et al. ICAAC 2005 Ibrahim et al. Antimicrob Agent Chemother 2005;49:721-727. Padera et al. Antimicrob Agent Chemother 2004;48:3845

  20. Efficacy of High-Dose Echinocandin Therapy + Other Licensed Antifungal Therapy (OLAT) • Ratanatharathorn, et al. (ASH 2002) • Micafungin + existing antifungal in 85 BMT pts • 39% (28%) complete/partial response • No evidence of clear benefit with doses > 100 mg/day • Safdar, et al. (ICAAC 2005) • Retrospective study from 2002-2004 • 100 mg/day + OLAT vs. 50 mg/day + OLAT • No benefit seen at 4 weeks • Improved response in HD Caspo group at 12 weeks • OR 3.1; 1.09-8.61, P=0.035 • Impact of other variables (neutropenia, OLAT)? • No major impact on toxicity

  21. Echinocandin Dosage Escalation-Summary Little evidence as of yet to suggest: Clinical benefit in invasive candidiasis or aspergillosis Clinical significance of a paradoxical effect Potential opportunities for infrequent dosing?

  22. What are the Risks/Benefits of Escalating Amphotericin B? • Safety: • Ambisome > Abelcet >Amphotec >>> Amphotericin B deoxycholate • Dose-dependent nephrotoxicity, electrolyte disturbances, hepatic toxicity? • Predictable PK: • Dose-proportional increases in serum concentrations to a point…then decreases with changes in tissue distribution • i.e. Ambisome10 mg/kg • Concentration-dependent PD: • Concentration-dependent activity in vitro and in vivo (some animal models)

  23. Theoretical maximum free drug serum concentration: 744 ng/mL Protein Binding/Poor Solubility May Confound Interpretation of Amphotericin B Pharmacodynamics • Poor solubility and high protein binding may create a relatively low ceiling effect for concentration-dependent activity • Only a fraction of AMB is bioactive in tissues • Concentrations of bioactive drug in aqueous homogenates < 20-40% of total drug measured by HPLC • Nephrotoxicity of conventional AMB can be correlated with infusion rate Bekersky et al. Antimicrob Agent Chemother 2002;46:834-840. Collette et al. Antimicrob Agents Chemother 1989;33: 362-36. Peleg and Woods. J Antimicrob Chemother 2004;54:803.

  24. Inflammation in the Lung DramaticallyDecreases Activity of AMB-deoxycholate Neutropenic Cortisone 30% less fungal burden; similar mortality Berenguer et al. Am J Respir Crit Care Med 1995;152:1079-1086 Balloy et al. Infection and Immunity 2005;73:494-503.

  25. Liposomal Amphotericin B is Superior to Amphotericin B Deoxycholate (AMB-d) in Reducing Inflammatory Lung Injury (ILI) and Fungal Burden in Corticosteroid-Treated Mice with Invasive Pulmonary Aspergillosis AMB-d 1 mg/kg L-AMB 10 mg/kg Lewis et al. ICAAC 2005

  26. Liposomal AmB1 mg/kg/d versus 4 mg/kg/d 1 mg/kg/d4 mg/kd/dp value (n=41) (n=46) Clinical CR + PR (inc. stable) 64% 48% 0.144 Radiologic CR + PR 58% 54% 0.694 6-month survival 43% 37% Overall deaths 59% 67% • Overall response rate of 55% • Overall 6-month mortality of 63% Ellis M, et al. Clin Infect Dis 1998;27:1406-12.

  27. A Randomized, Prospective Trial of a High-Loading Regimen vs. Standard Dosing (Ambiload) Patients with proven or probable IFI (n=201) L-AMB 10 mg/kg X 14 days (n=94) L-AMB 3 mg/kg X 14 days (n=107) blinded L-AMB 3 mg/kg Until EOT EOT response and Survival at 12 weeks Corenely et al ASH 2005.

  28. Underlying Conditions (MITT) N (%) AmBi-3 mg/kg (n=107) AmBi-10 mg/kg (n=94) * Includes acute and chronic leukemia, lymphoma, myeloma, and MDS Corenely et al ASH 2005.

  29. Favorable Overall Response: All Patients and Subsets % Response No differences were statistically significant Corenely et al ASH 2005.

  30. Survival % Response No differences were statistically significant Corenely et al ASH 2005.

  31. AmBiLoad Trial: Laboratory Abnormalities (ITT Population) N (%) AmBi-3 mg/kg (n=107) AmBi-10 mg/kg (n=94) 1. Serum creatinine > 2x baseline 2. Treatment emergent grade 3 or 4 values of ALT, AST, alkaline phosphatase or bilirubin * Includes acute and chronic leukemia, lymphoma, myeloma, and MDS

  32. Amphotericin B Dosage Escalation-Summary No convincing evidence of benefit for higher doses than current recommendations Unanswered questions: (1) Zygomycosis (2) High-dose, infrequent regimens (I.e. 15 mg/kg 1x every week)

  33. Conclusions • Clearer picture of the PK:PD basis for antifungal dosing in common opportunistic mycoses • Current dosing recommendations are appropriate for most situations, however dosage escalation may be useful in select cases • Suspected insufficient drug exposure (i.e. PK drug interactions) • Laboratory guidance important (renal, hepatic function monitoring, serum drug levels, genotyping?) • Dosage escalation must always be weighed against potentially more effective strategies, especially in the refractory patient • Switching to other treatment alternatives • Combination therapy

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