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Getting antifungal drug levels right – why does it matter?

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Presentation on theme: "Getting antifungal drug levels right – why does it matter?"— Presentation transcript:

1 Getting antifungal drug levels right – why does it matter?
David Andes University of Wisconsin Recognizing that most drug effects are determined by the interplay of several gene products that govern the PK and PD of medications, PG research aims to elucidate these polygenic determinants of drug effects.

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 Voriconazole: Dose-versus-Concentration UN-Predictable
12 Time (hours) 1 2 3 4 5 6 7 8 9 10 11 1000 2000 3000 4000 5000 6000 7000 8000 Plasma voriconazole concentrations (ng/ml) Variable and unpredictable dose-concentration relationship for: Voriconazole, Itraconazole, Posaconazole Voriconazole exhibits wide intra- and intersubject variability in serum concentrations. Excellent bioavailability, estimated to be greater than 90%. Major enzymes involved in voriconazole metabolism include CYP2C9, CYP3A4, and CYP2C19. The latter is associated with significant inter-patient variability due to the genetic polymorphism of the enzyme. For example, approximately 15-20% of Asian populations and 3-5% of Caucasians and Blacks have been shown to be poor metabolizers. In patients who are poor metabolizers, voriconazole concentrations can be up to 4 times higher than those who are. Non-linear kinetics related to its saturable metabolism. Voriconazole serum concentrations are significantly reduced by many medications including, rifampin, carbamazepine, long-acting barbiturates, ritonavir, efavirenz, and rifabutin. Trifilio S, Ortiz R, Pennick G, et al. Voriconazole therapeutic drug monitoring in 654 allogeneic hematopoietic stem cell transplant recipients. Bone Marrow 655 Transplantation 2005; 35: Ikeda Y, Umemura K, Kondo K, et al. Pharmacokinetics of voriconazole and cytochrome 664 P450 2C19 genetic status. Clinical Pharmacology & Therapeutics 2004; 75: 587- 665 8.

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 (amount of drug) Concentration Minimum
therapeutic level Time

16 Itraconazole Therapeutic Window
Probability of toxicity Trough itraconazole concentrations mg/L 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 24:235-47, 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.

19 Factors That Impact Concentration

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

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

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

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

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

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 Measuring Antifungal Concentration
When? How Often?

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
Absorption Elimination Amount Itraconazole (pill) Give acidic beverage Stop acid reducing drugs Give with food Avoid inducing medications Yes (solution) Voriconazole Give on empty stomach Avoid inducing drugs Give inhibiting drug Posaconazole Give with fatty food Give more frequently

31 Should We Measure Antifungal Concentrations? YES
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 How Should We Do This? CONCLUSION 2
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 % 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: 69-75 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 Itraconazole Concentration Effect Prophylaxis
Neutropenic, itraconazole prophylaxis Itraconazole 200 mg/d HPLC % with invasive fungal infection In another prophylactic study, sustained itraconazole concentrations which were below 0.25 mg/L for 2 weeks were associated with a significantly higher incidence of invasive infections when compared to those with concentrations over 0.25 mg/L (66.6% versus 15.8%, p<0.001). 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 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 ± 4.2 11 nonresponders – mean peak 4.0 ± 3.2 Aspergillus n=21 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 Pharmacokinetics of Voriconazole - Influence of CYP2C19 genotype
1 2 3 4 5 6 7 8 Influence of CYP2C19 Genotype on Average Steady-State Plasma Voriconazole Concentrations Homozygous Extensive metabolizer (n=108) Heterozygous (n=39) Poor metabolizer (n=8) Serum Cav (mcg/mL) CYP2C19 is significantly involved in the metabolism of voriconazole Poor metabolizers have, on average, 4-fold higher voriconazole exposure Poor metabolizers: 15-20% of the Asian population and 3-5% of Caucasians and blacks Most frequent adverse event was visual disturbances 10 clinical trials identified positive associations between plasma voriconazole concentrations and incidence of both liver function test abnormalities and visual disturbances Hyland R, et al Identification of the cytochrome P450 enzymes involved in the N-oxidation ff voriconazole. Drug Metab Dispos. 31:540 FDA Advisory Committee Oct Voriconazole CYP2C19 Metabolism % Caucasian Population % Asian Poor 5 20 Heterozygous 45 Extensive 75 35

38 Voriconazole Concentration Effect Toxicodynamics - Liver
Observed Weekly Occurrences Model Estimates UPPER PRED LOWER Probability (%) Occurrence (%) Associations between adverse events and voriconazole serum concentrations have also been examined. An analysis of 10 studies summarized in the voriconazole product information reported a positive correlation between elevations in serum concentration with liver function test abnormalities and visual disturbances. In the study of patients with aspergillosis treated with voriconazole, 6/22 patients with plasma concentrations >6 mg/L experienced liver failure or deterioration in liver function. Increases in AST (r=0.50; p=0.0009) and alkaline phosphatase levels (r=0.34;p=0.03) were correlated with elevations of plasma voriconazole concentrations in adult allogeneic stem cell transplant recipients. Plasma voriconazole concentration category (g/ml) Plasma voriconazole concentration (g/ml) 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
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 Voriconazole Random Levels 3 mg/kg BID N=6 N=130 % Failures In a previous report of patients with aspergillosis treated with voriconazole, it was noted that 3 out of the 5 patients with serum voriconazole concentrations consistently less than mg/L failed to respond to therapy, 1 deteriorated then subsequently improved with an increased dose, and 1 had a stable response. Denning et al. Clin Infect Dis. 2002;34:563.

41 Voriconazole Concentration Effect Efficacy
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: Gubbins PO et al. Antimicrobial Agents Chemotherapy 2006; 50: Ullmann AJ et al. Antimicrobial Agents Chemotherapy 2006; 50:

43 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% Average Concentration (ng/mL) 500 1000 1500 2000 Posaconazole Pharmacokinetics in Febrile Neutropenic Patients Individual Average Concentrations Day 10 400 twice daily 600 twice daily 800 once daily Significant interpatient variability in pharmacokinetic parameters Absorption is increased times when the oral suspension is administered with a meal; with high-fat meals (approximately 50 grams of fat) enhancing absorption to the greatest extent. In a study of 98 patients with persistent febrile neutropenia or refractory invasive fungal infections, exposure to posaconazole was 52% lower in allogeneic bone marrow transplant recipients than non-bone marrow transplant patients. The average steady state peak concentrations were 0.851, 0.579, and mg/L for the 400mg twice daily, 600mg twice daily, and 800mg daily treatment groups, respectively. However, for each group these mean values were shown to be highly variable with reported coefficient of variations of 71 to 82 percent. In a study conducted in neutropenic stem cell transplant recipients, variability in thereported pharmacokinetic parameters ranged from 38-68% for all 346 dosing groups. The 200mg 347 daily, 400mg daily, and 200mg four times daily groups produced average steady-state peak 348 serum concentrations (± standard deviations) of (± 0.202), (± 0.166) and (± ) mg/L, respectively. 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: 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

44 Posaconazole Concentration Effect
Aspergillus and Patients (N=67) In a rabbit model of invasive aspergillosis, the same group showed a superior response in rabbits with sustained concentrations above 1.0 µg/mL [20]. Preclinical PD demonstrated target of 25 An open-label multicenter study of the efficacy and safety of posaconazole for the treatment of invasive aspergillosis in patients who were refractory to or intolerant of other antifungal therapy, reported that higher plasma concentrations were associated with improved response rates. During this study, posaconazole was dosed as 200mg orally four times daily while in the hospital and 400mg twice daily as an outpatient. When the mean maximum and average plasma concentrations were and mg/L, respectively, only 24% (4 of 17) of patients responded. Over 50% (18 of 34) of patients responded to therapy when the mean maximum and average plasma concentrations ranged from to mg/L and to mg/L, respectively. In contrast, when the mean maximum and average plasma concentrations rose to 1.48 and 1.25 mg/L, respectively, 75% (12 of 16) of the patients responded. Based on the limited data available, a maximum plasma concentration of >1.48 mg/L (or an average concentration of 1.25 mg/L) after approximately 5-7 days of therapy would be a reasonable serum concentration target 75% response in the quartile with the highest mean peak blood level (1.48 µg/mL) vs. 53% in the second (0.85 µg/mL) and third (0.47 µg/mL) quartiles and 24% in the lowest quartile (0.14 µg/mL) 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 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 Posaconazole TDM – San Antonio, Tx
78% < 0.92 ug/ml 66% <0.611 ug/ml 17.3% < ug/ml 70% < ug/ml Thompson et al AAC 2009;53:2223

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

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