Latest Developments in the Latest Developments in the Treatment of Invasive Treatment of Invasive

AspergillosisAspergillosis

William J. Steinbach, MD

Assistant Professor of Pediatrics, Molecular Genetics, and Microbiology

Pediatric Infectious Diseases

Duke University Medical Center

Durham, NC USA

Possible Areas for Improving Possible Areas for Improving Outcome in IAOutcome in IA

Understanding IA epidemiology Host factors: Underlying & concomitant diseases Immunosuppression / Corticosteroids Antifungal prophylaxis Early diagnosis Early therapy Antifungal resistance Antifungal therapies Immune reconstitution, Immunotherapy

Invasive Aspergillosis IncidenceInvasive Aspergillosis Incidence1990-1998 at FHCRC1990-1998 at FHCRC

Marr KA, et al. Marr KA, et al. Clin Infect Dis. Clin Infect Dis. 2002;34:909-917.2002;34:909-917.

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0019901990 19911991 19921992 19931993 19941994 19951995 19961996 19971997 19981998

Allograft recipientsAllograft recipients Autograft recipientsAutograft recipients

Invasive Aspergillosis Invasive Aspergillosis EpidemiologyEpidemiology

1990-1998 data from 533 total cases of IA

1990 1998 Autologous HSCT <1 % 5.3% Allogeneic HSCT 4% 12%

1993-95 1996-98 Non-fumigatus Aspergillus 18.3% 33.7%

Average median survival of 29 days after diagnosis

Marr KA, et al. Clin Infect Dis 2002;34:909-17Wald A, et al. J Infect Dis 1997;175:1459-66.

Probability of Developing Proven or Probability of Developing Proven or Probable IA among patients alive at day 40Probable IA among patients alive at day 40

Overall P = 0.001

Marr KA, et al. Blood 2002;100:4358-4366.

Corticosteroids as a Corticosteroids as a Risk FactorRisk Factor

Pharmacologic doses of hydrocortisone (10-6 M), equivalent to 20 mg IV

In vitro mean specific growth rate of A. fumigatus at 37° C increased by 40% (p=0.0001)

A. fumigatus doubling time increased to 48 minutes

Ng TTC, et al. Microbiology 1994;140:2475-79

Host Host Susceptibility Variations:Susceptibility Variations:Different Inbred Mouse StrainsDifferent Inbred Mouse Strains

Sensitive: CAST/Ei, C3H/HEJ, A/J, DBA/2J

Intermediate: MRL/MPJ, NZW/LAC

Resistant: BalbC/ByJ, AKR/J, Balb/C, 129/SVJ, C57BL/6

Zaas AK, et al. 7th European Conference on Fungal Genetics, 2004

Antifungal TherapyAntifungal Therapyfor Invasive Aspergillosisfor Invasive Aspergillosis

A. terreus A. terreus InfectionInfection

Murine model– Amphotericin B resistance confirmedGraybill JR, et al. Antimicrob Agents Chemother 2004;48:3715-19.

Review of 28 in vitro analyses, 9 animal models, and 60 previously reported clinical cases– AmB resistance shown in vitro and in vivoSteinbach WJ, et al. Antimicrob Agents Chemother 2004;48:3217-25.

Multicenter retrospective analysis of 83 cases (1997-2002)– Mortality at 12 weeks decreased in those who received voriconazole

(HR 0.29; 95% CI, 0.15-0.56) vs. AmBSteinbach WJ, et al. Clin Infect Dis 2004;39:192-8.

Aspergillosis Survival with Amphotericin B Aspergillosis Survival with Amphotericin B

by Site of Infectionby Site of Infection

Lin et al. Lin et al. Clin Infect Dis. Clin Infect Dis. 2001;32:358-366.2001;32:358-366.

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Pulmonary (n=83)Pulmonary (n=83)

00 3030 6060 9090 120120 150150 180180 210210 240240 270270 300300 330330 360360DaysDays

Aspergilloma (n=10)Aspergilloma (n=10)

Multi-site (n=11)Multi-site (n=11)

Sinusitis (n=17)Sinusitis (n=17)

CNS or Disseminated (n=35)CNS or Disseminated (n=35)

Outcomes Research: Treatment PracticesOutcomes Research: Treatment PracticesPatterson TF, et al. Patterson TF, et al. Medicine Medicine 2000;79:250-2602000;79:250-260

IA cases after 1990, most from 1994-1995 (595 total cases of IA) Asked for recent case records, non-sequential Lipid formulations of AmB investigational, so few received Outcome data from 34 patients with L-AmB excluded because patients

were in other clinical trials Few Combinations Used: AmB + 5-FC (2%)

AmB + Rifampin (2%)AmB + Itraconazole (3%)

Outcomes:AmB Itraconazole AmB Itraconazole

Pts treated 31% 10% 16%All pts CR 25% 40% 39%All pts PR 7% 17% 15%

Outcomes Research: Treatment PracticesOutcomes Research: Treatment Practices Denning DW, et al. Denning DW, et al. J Infect J Infect 1998;37:173-180.1998;37:173-180.

1993-1994 (123 total cases of IA) Monotherapy in 29 pts, “Combination” therapy in 91 pts

AmB Lipid AmB Itraconazole 5-FC75% 36% 40% 12%

Six month outcomes for IPA:Alive w/o IA Alive w/ IA Expired

AmB 14% 41% 46%Lipid AmB 23% 31% 46%AmB + Itra 28% 56% 15%Itra 33% 17% 50%

61% mortality within 28 days after diagnosis

Outcomes Research: Open LabelOutcomes Research: Open Label

Compassionate use itraconazole (125 patients)– Complete response 27%; Improved 36%

Stevens DA and Lee JY. Arch Intern Med 1997;157:1857-62.

Multicenter open label itraconazole (76 patients)– Complete or partial response 39%

Denning DW, et al. Am J Med 1994;97:135-144.

Open label ABLC (130 patients)– Complete or partial response 42%

Walsh TJ, et al. Clin Infect Dis 1998;26:1383-96.

Antifungal Pre-ExposureAntifungal Pre-Exposure Serial passages of 10 clinical isolates to fluconazole (x4)

– 4-fold increase in MFC (but not MIC) of Itraconazole and Voriconazole– Fluconazole pre-exposure attenuates Itraconazole/ Voriconazole

fungicidal activity, but no effect in AmB– XTT growth rates pre-exposed/no fluconazole were same

Liu W, et al. Antimicrob Agents Chemother 2003;47:3592-7.

In vitro pre-exposure of A. fumigatus to Itraconazole or Caspofungin resulted in enhanced activity for either, in contrast to antagonistic effect of sequential itraconazole then AmB– Suggests a preferential role for azole-Caspofungin

sequential combinations over azole-AmB regimensKontoyiannis DP, et al. Diag Microbiol Infect Dis 2003;47:415-9.

Aspergillus Aspergillus Antifungal Resistance ?Antifungal Resistance ? Itraconazole resistance described in 1997

Denning DW, et al. Antimicrob Agents Chemother 1997;41:1364-68.

Estimated 2.1% of > 900 A. fumigatus strains resistant to itraconazoleMoore CB, et al. J Infect 2000;41:203-20.

200 sequential A. fumigatus isolates from 26 immunocompromised patients

MICs similar pre- and post-treatment with AmB (n=100) or itraconazole (n=91)

Emergence of resistance while on antifungal therapy is likely low Genotypic diversity and sequential colonization with multiple

strains could explain low resistanceDannaoui, et al. J Med Microbiol 2004;53:129-134.

Voriconazole Fungicidal Activity Voriconazole Fungicidal Activity on on HyphaeHyphae

Previous in vitro studies examined killing of conidia and germinated conidia (sporelings)

But patients have hyphae growing

Voriconazole killed hyphae in both time- and concentration-dependent fashions– Kill curve and MTT cell wall viability testing

Voriconazole had better fungicidal activity against A. fumigatus hyphae than AmB at 48 hours– VCZ 1 ug/ml >95% killed on agar (AmB 1 ug/ml 70% killed)– VCZ 1 ug/ml 99% killed in broth (AmB 1 ug/ml 82% killed)

Krishnan S, et al. J Antimicrob Chemother ePub April 20005

Only Only Three Three Randomized Clinical Trials Randomized Clinical Trials

ever completed for the ever completed for the Treatment of Invasive Treatment of Invasive

AspergillosisAspergillosis

Global Comparative Aspergillosis Study (307/602)DRC-Assessed Success at Week 12 (MITT)

Voriconazole arm success = 52.8%; Amphotericin arm = 31.6%Difference (raw) = 21.2%, 95 % CI (9.9, 32.6)Difference (adjusted) = 21.8%, 95% CI (10.5, 33.0)

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76/144

42/133 Same outcome in each separate

protocol

Herbrecht R, et al. N Engl J Med 2002; 347:408-415

-20 -10 0 10 20 30 40 50 60

% Difference in Success Rates (95% CI)

Overall

Pulmonary

Extra Pulmonary

Allogeneic BMT

Autologous BMT / other hematological (e.g. leukemia)

Other immunosuppressed state (e.g. SOT, HIV/AIDS)

Neutropenic (ANC < 500)

Non-Neutropenic (ANC 500)

Probable IA

Global Comparative Aspergillosis Study (307/602) DRC-Assessed Success at Week 12 (MITT)

Herbrecht R, et al. N Engl J Med 2002; 347:408-415

Proven IA

0 14 28 42 56 70 840.0

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Global Comparative Aspergillosis Study (307/602) Time to Death (MITT)

Number of days of Therapy

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Amphotericin B +/- OLAT

Voriconazole +/- OLAT

Day 84 survival: Voriconazole arm 71%; Amphotericin B arm 58%Hazard ratio = 0.6095% CI (0.40, 0.89)

Herbrecht R, et al. N Engl J Med 2002; 347:408-415

ABCD (6 mg/kg/d) vs. AmB-D (1.0–1.5 mg/kg/d)ABCD (6 mg/kg/d) vs. AmB-D (1.0–1.5 mg/kg/d) Prospective, double-blind, randomized, controlled clinical trial, risk stratified before

randomization; 1993-1997ABCD AmB-DEvaluable Patients (n=50) (n=53)Therapeutic response 52% 50.9% p=0.96

(complete, partial, or stable)Overall Mortality 36% 45% p=0.4

Fungal Mortality 32% 26% p=0.7

Renal Toxicity 25% 49% p=0.002

Median time to renal toxicity 301 d 22 d p<0.001

Intent to Treat (n=88) (n=86)Complete Response 5.7% 3.5%Partial Response 6.8% 11.6%

ABCD equivalent efficacy and superior renal safety Study terminated early due to low accrual

Bowden R, et al. Clin Infect Dis 2002;35:359-66.

Liposomal AmBLiposomal AmB1 mg/kg/d versus 4 mg/kg/d1 mg/kg/d versus 4 mg/kg/d

1 mg/kg/d 4 mg/kd/d p 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.

Switching to Other Licensed TherapiesSwitching to Other Licensed Therapies Received OLT in Voriconazole vs. AmB

– Initial VCZ 36% (52/144)– Initial AmB 80% (107/133)

159 total patients received OLT– 38% Lipid AmB formulation– 33% Itraconazole– 21% AmB deoxycholate (inc. reduced dose)– 8% Other antifungals

Switches due to Intolerance/Insufficient response– VCZ 24% (35/144) after median 12 days (1-83 days)– AmB 70% (93/133) after median 9 days (1-74 days)

(p<0.000001)Boucher HW, et al. ICAAC 2003, Abstract M-964

Use the Best Therapy FirstUse the Best Therapy First

Patient Success– 33% (31/93) AmB receiving OLT– 30% (14/47) AmB followed by lipid AmB (median 13 days)– 53% All randomized to VCZ (p<0.01)

Strategy of Voriconazole followed by OLT for intolerance or insufficient response was more successful than AmB with OLT (including lipid AmB)

Stresses the importance of initial therapy of voriconazole for IA

Boucher HW, et al. ICAAC 2003, Abstract M-964

Early Treatment is CriticalEarly Treatment is Critical

Mortality when treatment started after diagnosis:

< 10 days 40%

> 11 days 90%Von Eiff, et al. Respiration 1995;62:241-7.

Voriconazole as Primary TherapyVoriconazole as Primary Therapy

Denning DW, et al. Clin Infect Dis 2002;34:563-71.

Therapy Complete Partial Stable Failure Total Primary 10 (17%) 25 (42%) 11 (18%) 14 (23%) 60 (52%)Salvage 6 (11%) 15 (27%) 13 (23%) 22 (39%) 56 (48%)

Echinocandin Activity on Echinocandin Activity on Aspergillus Aspergillus Hyphal TipHyphal Tip

• Caspofungin (0.3 ug/ml)-treated, DiBAC-stained A. fumigatus• 6 hours incubation• 2,000X magnification

Bowman JC, et al. Antimicrob Agents Chemother 2002;46:3001-3012.

Caspofungin Salvage TherapyCaspofungin Salvage Therapy Open, non-comparative, multi-center trial 90 patients with IA enrolled (median 51 yrs; 15-73) Efficacy evaluation of 83 patients

– 71 patients (86%) refractory to therapy– 12 patients (14%) intolerant to therapy

45% (37/83) with favorable outcome– 50% (32/64) with pulmonary IA– 23% (3/13) with disseminated IA

Maertens J, et al. Clin Infect Dis 2004; 39:1563-71.

46 Neutropenic patients with IA Favorable response (35%)

– 42% as primary therapy– 32% as salvage therapy

Kartsonis N, et al. 14th ECCMID, Abstract 0422

Concentration-Dependent Concentration-Dependent Caspofungin ActivityCaspofungin Activity

Murine model of pulmonary IA– Substantial differences in fungal burden as determined by

qPCR – Largest reduction in burden by those dosing regimens

achieving the highest peak concentrations– Histological apical hyphal damage most at highest dose

Trend toward improving survival with maximal dosing Paradoxical “Eagle Effect” at highest dose, with an increase in

tissue burden (but no decrease in survival)– Same effect seen in other cell-wall active antibacterials

Wiederhold NP, et al. J Infect Dis 2004;190:1464-71.

Micafungin Monotherapy Micafungin Monotherapy Open-Label Trial in JapanOpen-Label Trial in Japan

70 patients at 29 sites; 56 pts eval. for efficacy (IA = 42)

Disease Response

Invasive pulmonary (n=10) 60%

(8 pts with leukemia or lymphoma; 2 neutropenic)

Max dose 50 mg/d 50% (1/2)

75 mg/d 33% (1/3)

150 mg/d 80% (4/5)

Disseminated (n=1) 0%

Chronic necrotizing pulmonary (n=9) 67%

Pulmonary aspergilloma (n=22) 55%

AE related to micafungin reported in 30% of patientsKohno S, et al. Scand J Infect Dis 2004;36:372-9.

Posaconazole MonotherapyPosaconazole Monotherapy Multicenter study for salvage therapy

– Included 25 pts with IA– Effective in 53% (8/15) at week 4– Effective in 85% (6/7) at week 8– No mention of patients without complete follow-up

Hachem RY, et al. ICAAC 2000, Abstract 1109

Multi-center study of patients with IA refractory to or intolerant of AmB formulations and itraconazole– 107 posaconazole, 86 controls– Global response rate at end of treatment

Posaconazole 42% Controls 26%

Walsh TJ, et al. ASH 2003, Abstract 682

Cerebral AspergillosisCerebral Aspergillosis 86 patients (9 mo - 81yo) with proven or probable CNS aspergillosis

– A. fumigatus (n=34); A. nidulans (n=5); Aspergillus spp. (n=24) Underlying disease

– BMT (n=33); Hem malignancy (n=14)– SOT (n=12); Acquired/Cong immunosuppression (n=15)– Other (n=12)

Only 13/86 received VCZ primary therapy

(others with previous antifungal therapy before VCZ use) Global Clinical Outcome

– Complete / Partial Response 34%– Stable / Failed response 66%– BMT Recipient Response 15%– All Others Response 42-50%

Troke PF, et al. ICAAC 2003, Abstract M-1755

Bone AspergillosisBone Aspergillosis 20 patients from Clinical trials and Compassionate use Bone Involvement

– Spondylodiscitis (n=9); Sternum/Rib (n=6); Peripheral (n=5) Immunocompromised (n=14)

– Largest population: Chronic Granulomatous Disease (n=5) Bone was the only infection site in 10 patients Salvage voriconazole therapy in 18/20 patients Median duration of voriconazole 83.5 days (4-395 days)

Global Clinical Outcome Complete / Partial Response 55% (11/20)

– Complete (n=4); Partial (n=7), Failure (n=9)

Mouas H, et al. Clin Infect Dis 2005;40:1141-7.

Combination Antifungal Combination Antifungal TherapyTherapy

in Invasive Aspergillosisin Invasive Aspergillosis

Combination Therapy RationaleCombination Therapy Rationale

Widened spectrum and potency More rapid antifungal effect Additive or synergistic efficacy effects Lowered dosing or less toxicity Reduce risk of emerging resistance Historic poor outcomes with monotherapy Increased penetration / transport Inhibit different stages of the same biochemical

pathway Simultaneous inhibition of different fungal targets Creation of a fungicidal combination

1966-2001 Review of 1966-2001 Review of Combination TherapyCombination Therapy

Studies Syn Add Indiff Antag

In vitro (n=28) 36% 24% 28% 11%

In vivo (n=18) 14% 20% 51% 14%

AmB + Itraconazole generally indifferent interactions in vitro, in vivo, and clinically

249 cases met combination Rx inclusion criteria Most common combinations:

– AmB + Flucytosine (49%)– AmB + Itraconazole (16%)– AmB + Rifampin (11%)

Overall 63% of clinical cases reported improvementSteinbach WJ, et al. Clin Infect Dis 2003;37 (suppl 3): S188-224

Only Clinical Trial of Combination Only Clinical Trial of Combination Antifungal Therapy for AspergillosisAntifungal Therapy for Aspergillosis

28 neutropenic adult pts with proven IFI– AmB (0.5 mg/kg/d) (n=14)– AmB + 5-FC (n=14)

Survival:– AmB alone: 2/14 (mortality 86%)– AmB + 5-FC: 3/14 (mortality 79%)– 15/18 with invasive aspergillosis died– 3 who survived had immune recovery

Study terminated early, problems included:– IA so far advanced at initiation– Low dose AmB used

Verweij PE, et al. Infection 1994;22:81-5.

Experimental:Experimental:Voriconazole + CaspofunginVoriconazole + Caspofungin

In Vitro– 48 isolates, Synergy (87.5%) of interactions (FICI < 1.0)

Perea S, et al. Antimicrob Agents Chemother 2002;46:3039-41

In Vivo: Neutropenic guinea pig model– Mortality (0/12 animals) and survival time (8 days) SAME in EACH of

these arms: VCZ 5mg/kg/d CAS (1 mg/kg/d) + VCZ CAS (2.5 mg/kg/d) + VCZ

– Fungal burden (CFU) with combination better than untreated controls only

– Number of organs with positive cultures with combination better than monotherapy

Kirkpatrick WR, et al. Antimicrob Agents Chemother 2002;46:2564-8

Experimental:Experimental:Ravuconazole + MicafunginRavuconazole + Micafungin

Neutropenic rabbit model– Survival

Micafungin monotherapy (0/8) Ravuconazole monotherapy (2/8) Micafungin + Ravuconazole (9/12)

– Fungal burden, GM assay, Pulmonary injury, Pulmonary infiltrates all less in the combination

Petraitis V, et al. J Infect Dis 2003;187:1834-43

Ravuconazole + MicafunginRavuconazole + Micafungin

Petraitis V, et al. J Infect Dis 2003;187:1834-43

Ravuconazole + Micafungin Hyphal DamageRavuconazole + Micafungin Hyphal Damage

• The spherical chlamydoconidial structures are evidence of the effect of echinocandins• The focal hyphal disintegration and disruption are compatible with the effects of triazoles• Original magnification ×630; Insert, ×1000; Scale bar 20 um

Petraitis V, et al. J Infect Dis 2003;187:1834-43

Untreated Control

Micafungin

Ravuconazole Ravuconazole + Micafungin

Clinical Combination Therapy ReportsClinical Combination Therapy Reports Caspofungin + L-AmB salvage after previous L-AmB (n=48)

– Overall response rate 42%; Response in progressive IA 18%Kontoyiannis DP, et al. Cancer 2003;15:292-9

Micafungin + existing antifungal in 85 BMT pts– 39% (28%) complete/partial response

Ratanatharathorn V, et al. ASH 2002, Abstract A-2472

Open-label Micafungin salvage therapy in 283 patients– In salvage patients (IA, >7d prior therapy & >7d micafungin)

11/49 (22%) allogeneic HSCT responded

22/45 (49%) leukemia patients respondedUllman AJ, et al. ECCMID 2003, Abstract 0400

Salvage therapy with posaconazole– Posaconazole 29%– AmB lipid 8% (p=0.01)

– AmB lipid + Itraconazole 16% (p=0.2)

Raad II, et al. IDSA 2004, Abstract 678

Voriconazole + TerbinafineVoriconazole + Terbinafine

Previously reported in vitro synergistic/additive effect with terbinafine against Aspergillus

Immunosuppressed rat model A. fumigatus – AmB 1 mg/kg/d– VCZ 6 or 9 mg/kg/d– Terbinafine 150 mg/kg/d

VCZ 9 mg/kg/d (41%) increased survival over AmB (28%) (p< 0.05)

All treatment groups except AmB significantly increased survival compared to Terbinafine (13%)

Addition of Terbinafine to VCZ did not improve survival Combination reduced fungal counts compared to control and AmB

Gavalda J, et al. ICAAC 2004, Abstract M-224

New Data:New Data:Combination Therapy for IACombination Therapy for IA

47 patients with proven/probable IA from 1997-2001 Patients experienced failure of initial therapy with AmB

formulations Received either voriconazole (n=31) or voriconazole +

caspofungin (n=16) as salvage therapy Voriconazole + Caspofungin with improved 3-month survival

rate compared to voriconazole monotherapy (HR 0.42; 95% CI 0.17-1.1; p=0.048)

Multivariate model, combination with reduced mortality (HR 0.28; 95% CI 0.28-0.92; p=0.11)

Marr KA, et al. Clin Infect Dis 2004;39:797-802.

Voriconazole vs. Voriconazole + Caspofungin

Kaplan-Meier probability of survival after diagnosis P = .048, calculated from the likelihood ratio test using Cox regression

Marr KA, et al. Clin Infect Dis 2004;39:797-802.

Primary Combination TherapyPrimary Combination Therapy

Retrospective single center cohort review of consecutive patients with IA and an underlying hematologic malignancy (Jan 98 – July 03)

Proven (n=17) / Probable (n=17) / Possible (n=11) by EORTC/MSG Data presented below for Proven / Probable cases only

ALL Combo Mono P value

(n=34) (n=10) (n=24)

12 wk Survival 53% 50% 54% 0.82

Median Survival (d) 110 102 115 ---

CR/PR 41% 50% 37.5% 0.5

Stable 5.9% 0% 8.3% --

Failure 53% 50% 54% 0.86

No differences in survival between primary therapy with mono vs. comboMunoz LS, et al. ICAAC 2004, Abstract M-1024

In Vitro In Vitro Treatment PRIOR to Treatment PRIOR to Combination Antifungal TherapyCombination Antifungal Therapy

Subinhibitory concentration of AmB against Caspo + Vori or Caspo + Ravuconazole

Percentage of further reduction in growth following AmB addition

AmB 0.1 ug/ml AmB 0.2 ug/ml Caspo + VCZ 33% (14-57%) 34% (13-59%) Caspo + RVZ 11% (0-30%) 28% (16-48%)

Significant for all species except A. terreus for Cas/VCZ and A. fumigatus Cas/RVZ at AmB 0.1 ug/ml

FICI (0.5-1.9) for each triple combination improved by adding subinhibitory concentration of AmB – additive to indifferent effect

O’Shaughnessy EM, et al. ICAAC 2004, Abstract M-249

Pediatric Antifungal DataPediatric Antifungal Data

Pediatric VoriconazolePediatric Voriconazole

Elimination by Linear pharmacokinetics in children following doses of 3 and 4 mg/kg/q12h

Single dose, Open, two center study in UK– 11 Children ages 2-11 yrs (mean 5.9 yrs)

Multiple dose, Open, 8 center, two-cohort (ages 2-6, 6-12)– 28 children, mean age 6.4 yrs

Higher elimination capacity on a weight basis than do adult healthy volunteers

Walsh TJ, et al. Antimicrob Agents Chemother 2004;48:2166-72.

Pediatric VoriconazolePediatric Voriconazole

Extrapolated plasma pharmacokinetics of pediatric doses (5-12 mg/kg/q12h) vs. adult (4 mg/kg/q12h)– Pediatric dose of approx. 11 mg/kg/q12h is

equivalent to adult dose of 4 mg/kg/q12h by AUC and plasma concentration

– This is only valid if linear pharmacokinetics maintained throughout full dosage range

Walsh TJ, et al. Antimicrob Agents Chemother 2004;48:2166-72.

Correct pediatric dosing not fully established, but clearly higher than adult dosing – prompted a second PK study

22ndnd Pediatric Voriconazole Pediatric Voriconazole Pharmacokinetic StudyPharmacokinetic Study

Study completed, data analyses ongoing

PK study (2-12 yo) to evaluate > 4 mg/kg BID dosing– Enrolled 48 (39 completed all three PK periods)– Doses of 4, 6, 8 mg/kg/q12h– Each child received at least two different doses in

escalating order, then switched to PO

Oral Suspension (40 mg/ml) – FDA approved 12/24/03, orange flavor

Voriconazole for Pediatric AspergillosisVoriconazole for Pediatric Aspergillosis

Compassionate Use; 58 IFI including 42 IA Mean age 8.2 yrs (9 mo – 15 yrs) Therapeutic response

– Complete or partial response 43% Pulmonary IA (n=12) 33% CNS (n=6) 50% Disseminated (n=7) 86% Sinusitis (n=7) 29% Bone / Liver / Skin (n=10) 30%

– Stable 7%– Intolerance 10%– Failure 40%

Walsh TJ, et al. Pediatr Infect Dis J 2002;21:240-8.

Pediatric CaspofunginPediatric Caspofungin Adult dosing: Load 70mg once, then 50mg once daily

Initial pediatric (ages 2-17) PK study completed– 39 patients enrolled– Data obtained using a weight-based (1 mg/kg/d) and BSA

approach (70 mg/m2/d or 50 mg/m2/d)

Weight-based (1 mg/kg/d) resulted in suboptimal plasma concentrations in all children relative to adults

50 mg/m2/d similar C24hr and increased AUC to adult patients (50 mg/d)

Walsh TJ, et al. ICAAC 2002, Abstract M-896; Under review.

Pediatric CaspofunginPediatric Caspofungin

Caspofungin well-tolerated, no discontinuation due to toxicity

Beta-phase half-life reduced 32-43% in children, so plasma levels were lower

Subsequent studies in children 2-17 years old evaluating:– Load with 70 mg/m2 (max 70 mg/d) on Day 1

– Then, 50 mg/m2 (max 70 mg/d)

Walsh TJ, et al. ICAAC 2002, Abstract M-896; Under review.

SummarySummary

Aspergillus epidemiology changing GM assay interpretations different in specific populations Aspergillus qPCR still debated for diagnosis

Echinocandins unlikely to be best monotherapy (fungistatic against Aspergillus)

Voriconazole is clearly the best monotherapy Voriconzole primary therapy better than salvage therapy Voriconazole has linear pharmacokinetics in children

Combination therapy – unproven– Reports are often contradictory– Potentially would be best if used as primary therapy