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 AndesUniversity of WisconsinRecognizing 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 ManagementVoriconazoleItraconazolePosaconazole
3 Antifungal Administration Concentration mattersFactors that impact concentrationManaging concentration
5 Voriconazole: Dose-versus-Concentration UN-Predictable 12Time (hours)123456789101110002000300040005000600070008000Plasma voriconazole concentrations (ng/ml)Variable and unpredictabledose-concentration relationship for: Voriconazole,Itraconazole,PosaconazoleVoriconazole 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 in654 allogeneic hematopoietic stem cell transplant recipients. Bone Marrow655 Transplantation 2005; 35: Ikeda Y, Umemura K, Kondo K, et al. Pharmacokinetics of voriconazole and cytochrome664 P450 2C19 genetic status. Clinical Pharmacology & Therapeutics 2004; 75: 587-665 8.
6 Patient with Aspergillus Lung Infection LungsAspergillusStomachLiver
7 Patient with Aspergillus Lung Infection Taking Antifungal Medication
14 Voriconazole Concentration Effect Efficacy Smith et alN = 28 patient withAspergillosisPascual et alN = 52 patients withInvasive fungalinfectionsVoriconazole dose increased in11 patients with concentration< 2.0, 8 of 11 survivedSmith et al Antimicrob Agents Chemother 2006;50:1570–1572Pascual et al Clin Infect Dis 2008;46:201
16 Itraconazole Therapeutic Window Probability of toxicityTrough itraconazole concentrations mg/LTricot 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 ToxicityVoriconazole Trough ConcentrationDenning 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;53:958FDA.
28 Measuring Antifungal Concentration When and How Often? At the start of therapyAfter change in antifungal dose or formulationIf the aspergillus is getting worseIf I feel sick or have signs of antifungal toxicity
29 Concentration Management Optimize absorptionSometimes alter eliminationChange the antifungal dosing regimenChange the antifungal
30 Concentration Management Need to Increase Amount AbsorptionEliminationAmountItraconazole(pill)Give acidic beverageStop acid reducing drugsGive with foodAvoid inducing medicationsYes(solution)VoriconazoleGive on empty stomachAvoid inducing drugsGive inhibiting drugPosaconazoleGive with fatty foodGive more frequently
31 Should We Measure Antifungal Concentrations? YES CONCLUSION 1Should We Measure Antifungal Concentrations? YESThere is significant pharmacokinetic variability among many antifungal drugsThere are valid assays for all antifungalsThere 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 doingIf low, make sure absorption and elimination are optimizedIf still low, increase drug dose and re-measureIf still low, consider different drug
34 Itraconzole PK Variability Coefficient of variationNormal volunteers (n=5) 47%Patients (n=20) with leukemia %Patients (n=16) 15-fold variation in concentrationFormulation 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 stateLevels are assay dependentBioassay = both parent and active metaboliteHPLC = can measure both but provides parent aloneHardin TC, et al Antimicrob Agents Chemother 1988; 32:Lazo de la Vega S et al Drugs Under Exper Clin Res 1994; 20: 69-75Poirier 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 prophylaxisItraconazole 200 mg/dHPLC% with invasive fungal infectionIn 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% successHIV/AIDS cryptococcal meningitis n=25HPLC assay> 1 ug/ml 100% clinical response< 1 ug/ml 66% partial responseCoccidioidomycosis n=39Bioassay28 responders – mean peak 6.5 ± 4.211 nonresponders – mean peak 4.0 ± 3.2Aspergillus n=21Responders mean peak 7.5Nonresponders mean peak 4.2Rex et al. (1997). Clin Infect Dis 24:235-47Denning, DW et al (1989) Arch Intern Med 149,2301–8.Tucker, RM et al. (1990). J Amer Acad Derm 23, 593–601Denning, DW et al (1989). Amer J Med 86, 791–800
37 Pharmacokinetics of Voriconazole - Influence of CYP2C19 genotype 12345678Influence of CYP2C19 Genotypeon Average Steady-State PlasmaVoriconazole ConcentrationsHomozygousExtensive metabolizer(n=108)Heterozygous(n=39)Poormetabolizer(n=8)Serum Cav (mcg/mL)CYP2C19 is significantly involved in the metabolism of voriconazolePoor metabolizers have, on average, 4-fold higher voriconazole exposurePoor metabolizers: 15-20% of the Asian population and 3-5% of Caucasians and blacksMost frequent adverse event was visual disturbances10 clinical trials identified positive associations between plasma voriconazole concentrations and incidence of both liver function test abnormalities and visual disturbancesHyland R, et al Identification of the cytochrome P450 enzymes involved in the N-oxidation ff voriconazole.Drug Metab Dispos. 31:540FDA Advisory Committee Oct VoriconazoleCYP2C19Metabolism% CaucasianPopulation% AsianPoor520Heterozygous45Extensive7535
38 Voriconazole Concentration Effect Toxicodynamics - Liver Observed Weekly OccurrencesModel EstimatesUPPER PRED LOWERProbability (%)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)FDA.govUeda et al Int J Hematol Apr 2. [Epub ahead of printMatsumoto 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 aspergillosis142 patientsVoriconazole serum concentration monitoring in all (random)Range < 0.1 ug/ml to 9.7 ug/ml4% < 0.25 ug/ml, 8% ≤ 0.5 ug/mlVoriconazole Random Levels 3 mg/kg BIDN=6N=130% FailuresIn 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 patientsTrough concentrations ≥22/3 Aspergillosis1/3 Febrile neutropeniap<0.002Okuda et al Yakugaku Sasshi 2008;128:1811
42 Posaconazole PK Variability 300 patientsNo dosing informationNo timing informationJ. Wheat MiraVista Lab, personal communicationCourtney 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 partdue to variable absorptionCoefficient of variation 40-80%clinical trialsLower concentrations in patients(52% lower) than healthy volunteersIncreased with fractionationIncreased with food (> fat) by3-4 XSignificant reduction in AUC (50%)with reduced gastric acidity (PPI, etc)Acidic beverage increases AUC 92%Average Concentration (ng/mL)500100015002000Posaconazole Pharmacokinetics in Febrile Neutropenic Patients Individual AverageConcentrations Day 10400 twice daily600 twice daily800 once dailySignificant interpatient variability in pharmacokinetic parametersAbsorption 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 .Preclinical PD demonstrated target of 25An 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 target75% 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 GVHDAverage level in those with IFI ug/mlAverage level in those without IFI ug/mlFDA GuidanceGoal = average concentration > ug/mlKrishna et al Pharmacotherapy 2009;53:958FDA.
46 Posaconazole TDM – San Antonio, Tx 78% < 0.92 ug/ml66% <0.611 ug/ml17.3% < ug/ml70% < ug/mlThompson et al AAC 2009;53:2223
47 Antifungal TDM Recommendations Andes et al AAC 2009;53:24