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

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Presentation on theme: "Getting antifungal drug levels right – why does it matter? David Andes University of Wisconsin."— Presentation transcript:

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-Concentration Predictable Concentration (AUC)

5 12 Time (hours) Plasma voriconazole concentrations (ng/ml) Voriconazole: Dose-versus-Concentration UN-Predictable 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

10 Antifungal Working

11 Too Little Antifungal

12 Too Much Antifungal Drug

13 Concentration Matters

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

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

16 Tricot G et al. (1987). RID Suppl. 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: , 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 Probability of toxicity Trough itraconazole concentrations mg/L Itraconazole Therapeutic Window

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

18 Posaconazole Therapeutic Window ? Walsh et al CID 2007, Krishna et al Pharmacotherapy 2009;53:958 FDA.

19 Factors That Impact Concentration

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

21 Amount Absorbed Food EffectStomach Acid Effect Itraconazole (pill) (Acid reducing drugs decrease absorption) Itraconazole (liquid) Voriconazole Posaconazole (fat best) (Acid reducing drugs decrease absorption)

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

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

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

25 Amount Eliminated Liver Enzymes (Genetics) Other Drugs Block Enzymes Other Drugs Enhance Enzymes Itraconazole (pill or liquid) Voriconazole++++ (major cause for variation) Posaconazole+++

26 Managing Concentration

27 When? How Often? Measuring Antifungal Concentration

28 Measuring Antifungal Concentration When 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 Management Need to Increase Amount AbsorptionEliminationAmount Itraconazole (pill) Give acidic beverage Stop acid reducing drugs Give with food Avoid inducing medications Yes Itraconazole (solution) Avoid inducing medications Yes Voriconazole Give on empty stomach Avoid inducing drugs Give inhibiting drug Yes Posaconazole Give with fatty food Give acidic beverage Stop acid reducing drugs Give more frequently Avoid inducing drugsYes

31 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 CONCLUSION 1

32 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 CONCLUSION 2

33 Backup Slides

34 Itraconzole PK Variability Coefficient of variation –Normal volunteers (n=5) 47% –Patients (n=20) with leukemia % –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: Lazo de la Vega S et al Drugs Under Exper Clin Res 1994; 20: Poirier JM et al. Therapie 1996; 51: , Van Peer A et al. Eur J Clin Pharmacol 1989; 36: Jaruratanasirikul S. Eur J Clin Pharmacol 1997; 52:235-7., Van de Velde VJ et al. Pharmacotherapy 1996; 16: Cartledge JD et al. J Clin Path 1997; 50:

35 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 Itraconazole Concentration Effect Prophylaxis

36 Itraconazole Concentration Effect Treatment 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 ± 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: 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 Pharmacokinetics of Voriconazole - Influence of CYP2C19 genotype Influence of CYP2C19 Genotype on Average Steady-State Plasma Voriconazole Concentrations Homozygous Extensive metabolizer (n=108) Heterozygous Extensive metabolizer (n=39) Homozygous Poor metabolizer (n=8) Serum C av (mcg/mL) CYP2C19 Metabolism % Caucasian Population % Asian Population Poor520 Heterozygous2045 Extensive7535

38 Voriconazole Concentration Effect Toxicodynamics - Liver Observed Weekly OccurrencesModel Estimates UPPER PRED LOWER Occurrence (%) Plasma voriconazole concentration ( g/ml) Plasma voriconazole concentration category ( g/ml) Probability (%) FDA.gov Ueda et al Int J Hematol Apr 2. [Epub ahead of print Matsumoto et al Int J Antimicrob Agents Mar 2. [Epub ahead of print]

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

40 Voriconazole Concentration Effect Efficacy Voriconazole Random Levels 3 mg/kg BID N=6 N=130 % Failures Denning et al. Clin Infect Dis. 2002;34:563. 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

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

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: Gubbins PO et al. Antimicrobial Agents Chemotherapy 2006; 50: Ullmann AJ et al. Antimicrobial Agents Chemotherapy 2006; 50:

43 Posaconazole PK Variability Average Concentration (ng/mL) Posaconazole Pharmacokinetics in Febrile Neutropenic Patients Individual Average Concentrations Day twice daily 600 twice daily 800 once daily Ullmann AJ et al. Antimicrob Agents Chemother. 2006;50: 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 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%

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

45 Posaconazole Concentration Effect IFI Prophylaxis in GVHD –Average level in those with IFI ug/ml –Average level in those without IFI ug/ml FDA Guidance –Goal = average concentration > ug/ml Krishna et al Pharmacotherapy 2009;53:958 FDA.

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

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


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