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Getting antifungal drug levels right – why does it matter?

Getting antifungal drug levels right – why does it matter?. David Andes University of Wisconsin. Antifungal Therapy and Aspergillus. Drugs That May Need Concentration Management Voriconazole Itraconazole Posaconazole. Antifungal Administration. Concentration matters

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Getting antifungal drug levels right – why does it matter?

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  1. Getting antifungal drug levels right – why does it matter? David Andes University of Wisconsin

  2. Antifungal Therapy and Aspergillus Drugs That May Need Concentration Management • Voriconazole • Itraconazole • Posaconazole

  3. Antifungal Administration • Concentration matters • Factors that impact concentration • Managing concentration

  4. Fluconazole: Dose-versus-ConcentrationPredictable Concentration (AUC)

  5. Voriconazole: Dose-versus-ConcentrationUN-Predictable 8000 7000 6000 5000 4000 Plasma voriconazole concentrations (ng/ml) 3000 2000 1000 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (hours) Variable and unpredictable dose-concentration relationship for: Voriconazole, Itraconazole, Posaconazole

  6. Patient with Aspergillus Lung Infection Lungs Aspergillus Stomach Liver

  7. Patient with Aspergillus Lung Infection Taking Antifungal Medication

  8. Absorbing Antifungal

  9. Absorbing Antifungal

  10. Antifungal Working

  11. Too Little Antifungal

  12. Too Much Antifungal Drug

  13. Concentration Matters

  14. Voriconazole Concentration Effect Efficacy • Smith et al • N = 28 patient with • Aspergillosis • Pascual et al • N = 52 patients with • Invasive fungal • infections Voriconazole dose increased in 11 patients with concentration < 2.0, 8 of 11 survived Smith et al Antimicrob Agents Chemother 2006;50:1570–1572 Pascual et al Clin Infect Dis 2008;46:201

  15. Therapeutic Window Toxic level Concentration (amount of drug) Minimum therapeutic level Time

  16. Itraconazole Therapeutic Window Probability of toxicity Trough itraconazole concentrations mg/L Tricot G et al. (1987). RIDSuppl. 1, S94–S99., Boogaerts M. A. et al. (1989). Mycoses 32, Suppl. 1, 103–8., Glasmacher et al. Mycoses (1999) 42:443-9, Rex et al. (1997). CID 24:235-47, Denning, DW et al (1989) Arch Intern Med 149,2301–8., Tucker, RM et al. (1990). J Amer Acad Derm 23, 593–601, Denning, DW et al (1989). Amer J Med 86, 791–800, Lestner et al CID 2009

  17. Voriconazole Therapeutic Window Likelihood of Success or Toxicity Voriconazole Trough Concentration Denning et al, CID 2002, Smith et al AAC 2006, Pascual et al CID 2008, Okuda et al Yakugaku Sasshi 2008;128:1811

  18. Posaconazole Therapeutic Window ? Walsh et al CID 2007, Krishna et al Pharmacotherapy 2009;53:958 FDA. http://www.fda.gov/cder/foi/nda/2006/022003s333_NovafilTOC.htm

  19. Factors That Impact Concentration

  20. Absorption of Antifungal Drug from Gastrointestinal Tract GI tract/Stomach Antifungal Drug ABSORPTION

  21. Amount Absorbed

  22. Elimination of Antifungal Drug Via NORMAL Liver Metabolism Active Antifungal Inactive Antifungal

  23. Elimination of Antifungal Drug Via SLOW Liver Metabolism Active Antifungal Inactive Antifungal

  24. Elimination of Antifungal Drug Via FAST Liver Metabolism Active Antifungal Inactive Antifungal

  25. Amount Eliminated

  26. Managing Concentration

  27. Measuring Antifungal Concentration When? How Often?

  28. Measuring Antifungal ConcentrationWhen and How Often? • At the start of therapy • After change in antifungal dose or formulation • If the aspergillus is getting worse • If I feel sick or have signs of antifungal toxicity

  29. Concentration Management • Optimize absorption • Sometimes alter elimination • Change the antifungal dosing regimen • Change the antifungal

  30. Concentration ManagementNeed to Increase Amount

  31. CONCLUSION 1 Should We Measure Antifungal Concentrations? YES • There is significant pharmacokinetic variability among many antifungal drugs • There are valid assays for all antifungals • There are strong concentration toxicity and efficacy relationships for several antifungals

  32. CONCLUSION 2 How Should We Do This? • Measure concentration at start of therapy, with change in antifungal or with a change in how patient is doing • If low, make sure absorption and elimination are optimized • If still low, increase drug dose and re-measure • If still low, consider different drug

  33. Backup Slides

  34. Itraconzole PK Variability • Coefficient of variation • Normal volunteers (n=5) 47% • Patients (n=20) with leukemia 83-115% • Patients (n=16) 15-fold variation in concentration • Formulation dependent (capsule > solution) • Absorption of the capsule is pH dependent, requiring an acidic environment. Therefore, it is recommended to be given with a full meal or a cola. In contrast, absorption of the oral solution is enhanced in the fasted state • Levels are assay dependent • Bioassay = both parent and active metabolite • HPLC = can measure both but provides parent alone Hardin TC, et al Antimicrob Agents Chemother 1988; 32: 1310-3 Lazo de la Vega S et al Drugs Under Exper Clin Res 1994; 20: 69-75 Poirier JM et al. Therapie 1996; 51: 163-7., Van Peer A et al. Eur J Clin Pharmacol 1989; 36: 423-6. Jaruratanasirikul S. Eur J Clin Pharmacol 1997; 52:235-7., Van de Velde VJ et al. Pharmacotherapy 1996; 16: 424-8. Cartledge JD et al. J Clin Path 1997; 50: 477-80

  35. Itraconazole Concentration EffectProphylaxis • Neutropenic, itraconazole prophylaxis • Itraconazole 200 mg/d • HPLC • % with invasive fungal infection 1] Tricot G et al. (1987). Reviews of Infectious Diseases 9, Suppl. 1, S94–S99. 2] Boogaerts M. A. et al. (1989). Mycoses 32, Suppl. 1, 103–8. 3] Glasmacher et al. Mycoses (1999) 42:443-9

  36. Itraconazole Concentration EffectTreatment • Mucosal candidiasis n=264 from 4 trials > 0.5 ug/ml 65-89% success (range dependent on MIC) < 0.5 ug/ml 44-88% success • HIV/AIDS cryptococcal meningitis n=25 HPLC assay > 1 ug/ml 100% clinical response < 1 ug/ml 66% partial response • Coccidioidomycosis n=39 Bioassay 28 responders – mean peak 6.5 ± 4.2 11 nonresponders – mean peak 4.0 ± 3.2 • Aspergillus n=21 Bioassay Responders mean peak 7.5 Nonresponders mean peak 4.2 Rex et al. (1997). Clin Infect Dis 24:235-47 Denning, DW et al (1989) Arch Intern Med 149,2301–8. Tucker, RM et al. (1990). J Amer Acad Derm 23, 593–601 Denning, DW et al (1989). Amer J Med 86, 791–800

  37. Influence of CYP2C19 Genotype on Average Steady-State Plasma Voriconazole Concentrations 8 CYP2C19 % Caucasian % Asian 7 Metabolism Population Population 6 Poor 5 20 5 Heterozygous 20 45 Serum Cav (mcg/mL) 4 Extensive 75 35 3 2 1 0 Homozygous Extensive metabolizer (n=108) Heterozygous Extensive metabolizer (n=39) Homozygous Poor metabolizer (n=8) Pharmacokinetics ofVoriconazole - Influence of CYP2C19 genotype

  38. UPPERPREDLOWER Voriconazole Concentration EffectToxicodynamics - Liver Observed Weekly Occurrences Model Estimates Probability (%) Occurrence (%) Plasma voriconazole concentration category (g/ml) Plasma voriconazole concentration (g/ml) FDA.gov Ueda et al Int J Hematol. 2009 Apr 2. [Epub ahead of print Matsumoto et al Int J Antimicrob Agents. 2009 Mar 2. [Epub ahead of print]

  39. Voriconazole Concentration EffectToxicodynamics CNS Toxicity Pascual et al Clin Infect Dis 2008;46:201

  40. Voriconazole Random Levels3 mg/kg BID % Failures N=6 N=6 N=130 Voriconazole Concentration EffectEfficacy • Prospective, open label voriconazole for invasive aspergillosis • 142 patients • Voriconazole serum concentration monitoring in all (random) • Range < 0.1 ug/ml to 9.7 ug/ml • 4% < 0.25 ug/ml, 8% ≤ 0.5 ug/ml Denning et al. Clin Infect Dis. 2002;34:563.

  41. Voriconazole Concentration EffectEfficacy • 21 patients • Trough concentrations ≥2 • 2/3 Aspergillosis • 1/3 Febrile neutropenia • p<0.002 Okuda et al Yakugaku Sasshi 2008;128:1811

  42. Posaconazole PK Variability • 300 patients • No dosing information • No timing information J. Wheat MiraVista Lab, personal communication Courtney R et al. British Journal of 699 Clinical Pharmacology 2004; 57: 218-22. Gubbins PO et al. Antimicrobial Agents Chemotherapy 2006; 50: 1993-9. Ullmann AJ et al. Antimicrobial Agents Chemotherapy 2006; 50: 658-66.

  43. Posaconazole Pharmacokinetics in Febrile Neutropenic PatientsIndividual Average Concentrations Day 10 2000 1500 1000 Average Concentration (ng/mL) 500 0 400 twicedaily 600 twicedaily 800 once daily Posaconazole PK Variability • Mechanism- at least in part • due to variable absorption • Coefficient of variation 40-80% • clinical trials • Lower concentrations in patients • (52% lower) than healthy volunteers • Increased with fractionation • Increased with food (> fat) by • 3-4 X • Significant reduction in AUC (50%) • with reduced gastric acidity (PPI, etc) • Acidic beverage increases AUC 92% Ullmann AJ et al. Antimicrob Agents Chemother. 2006;50:658-666 Kosoglou T et al J Clin Pharmacol 1990; 30:638–42. Jain R et al Clin Infect Dis 2008; 46:1627–8. Krishna et al AAC 2009;53:958

  44. Posaconazole Concentration Effect Aspergillus and Patients (N=67) Walsh TJ et al. Clinical Infectious Diseases 2007; 44: 2-12.

  45. Posaconazole Concentration Effect • IFI Prophylaxis in GVHD • Average level in those with IFI 0.611 ug/ml • Average level in those without IFI 0.922 ug/ml • FDA Guidance • Goal = average concentration > 0.700 ug/ml Krishna et al Pharmacotherapy 2009;53:958 FDA. http://www.fda.gov/cder/foi/nda/2006/022003s333_NovafilTOC.htm

  46. Posaconazole TDM – San Antonio, Tx • 78% < 0.92 ug/ml • 66% <0.611 ug/ml • 17.3% < 0.134 ug/ml • 70% < 0.700 ug/ml Thompson et al AAC 2009;53:2223

  47. Antifungal TDM Recommendations Andes et al AAC 2009;53:24

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