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Clinical Therapeutics

Pharmacokinetics, Safety, and Efficacy of Posaconazole in Patients with Persistent Febrile Neutropenia or Refractory Invasive Fungal Infection

A. J. Ullmann, O. A. Cornely, A. Burchardt, R. Hachem, D. P. Kontoyiannis, K. Töpelt, R. Courtney, D. Wexler, G. Krishna, M. Martinho, G. Corcoran, I. Raad
A. J. Ullmann
1Third Medical Department, Johannes Gutenberg-University, Mainz, Germany
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  • For correspondence: a.ullmann@3-med.klinik.uni-mainz.de
O. A. Cornely
2University of Köln, Köln, Germany
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A. Burchardt
1Third Medical Department, Johannes Gutenberg-University, Mainz, Germany
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R. Hachem
3The University of Texas MD Anderson Cancer Center, Houston, Texas
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D. P. Kontoyiannis
3The University of Texas MD Anderson Cancer Center, Houston, Texas
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K. Töpelt
2University of Köln, Köln, Germany
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R. Courtney
4Schering-Plough Research Institute, Kenilworth, New Jersey
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D. Wexler
4Schering-Plough Research Institute, Kenilworth, New Jersey
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G. Krishna
4Schering-Plough Research Institute, Kenilworth, New Jersey
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M. Martinho
4Schering-Plough Research Institute, Kenilworth, New Jersey
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G. Corcoran
4Schering-Plough Research Institute, Kenilworth, New Jersey
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I. Raad
3The University of Texas MD Anderson Cancer Center, Houston, Texas
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DOI: 10.1128/AAC.50.2.658-666.2006
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  • FIG. 1.
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    FIG. 1.

    Individual average concentrations (natural log scale) of posaconazole at days 3 (top) and 10 (bottom) for each dosage regimen. The horizontal lines indicate mean values.

  • FIG. 2.
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    FIG. 2.

    Mean posaconazole plasma concentration-time profile on day 10 in patients receiving 400 mg b.i.d., 600 mg b.i.d., or 800 mg q.d. posaconazole oral suspension.

Tables

  • Figures
  • TABLE 1.

    Summary of patient demographic data

    CharacteristicValue
    Group 1 (200 mg q.i.d./ 400 mg b.i.d.) (n = 35)Group 2 (400 mg q.i.d./ 600 mg b.i.d.) (n = 31)Group 3 (800 mg b.i.d./ 800 mg q.d.) (n = 32)Total (n = 98)
    Mean age [yr (range)]45.3 (18-73)49.2 (20-73)51.2 (20-74)48.4 (18-74)
    Age (yr)
        ≥18 to <65 [n (%)]30 (86)27 (87)26 (81)83 (85)
        ≥65 [n (%)]5 (14)4 (13)6 (19)15 (15)
    Sex [n (%)]
        Female14 (40)14 (45)10 (31)38 (39)
        Male21 (60)17 (55)22 (69)60 (61)
    Race [n (%)]
        Caucasian32 (91)31 (100)27 (84)90 (92)
        Other3 (9)05 (16)8 (8)
    Mean wt [kg (range)]71.7 (49.8-111.0)74.6 (52.8-112.4)74.7 (49.3-101.0)73.6 (49.3-112.4)
    Primary diagnosis
        FN23 (66)21 (68)22 (69)66 (67)
        rIFI12 (34)10 (32)10 (31)32 (33)
  • TABLE 2.

    Posaconazole pharmacokinetic parameters on day 3

    Parameter (units)Value [mean (% coefficient of variation)]
    Group 1 (200 mg q.i.d.) (n = 24)Group 2 (400 mg q.i.d.) (n = 21)Group 3 (800 mg b.i.d.) (n = 24)
    C max (ng/ml)539 (82)531 (71)417 (60)
    C av (ng/ml)447 (84)423 (70)340 (63)
    T max a (h)2.65 (0, 11.8)5.78 (2, 12.4)4.21 (0, 11.9)
    AUC(0-12) (ng · h/ml)5,314 (83)5,075 (71)4,035 (63)
    • ↵ a Median (minimum, maximum).

  • TABLE 3.

    Posaconazole pharmacokinetic parameters on day 10

    Parameter (unit)aValue [mean (% coefficient of variation)]
    Group 1 (400 mg b.i.d.) (n = 24)Group 2 (600 mg b.i.d.) (n = 19)Group 3 (800 mg q.d.) (n = 18)
    C max (ng/ml)851 (82)579 (71)361 (74)
    C min (ng/ml)640 (98)388 (64)252 (100)
    C av (ng/ml)723 (86)490 (71)259 (72)
    C av, least square (ng/ml)523333184
    T max (h)b3.0 (0, 12.5)3.83 (0, 10)4.04 (2.42, 12.5)
    AUCτ (ng · h/ml)8,619 (86)5,823 (71)6,199 (71)
    NAUC (ng · h/ml)c8,619 (86)3,882 (71)3,099 (71)
    V/F (liters)2,447 (421)4,984 (919)5,061 (903)
    CL/F (liters/h)283 (354)179 (82)215 (81)
    T 1/2 (h)11.9 (3)12.0 (3)24 (2)
    • ↵ a C min, Trough plasma concentration; T1/2, half-life.

    • ↵ b Median (minimum, maximum).

    • ↵ c P value for log-transformed NAUC: 400 mg b.i.d. versus 600 mg b.i.d., P = 0.0004; 400 mg b.i.d. versus 800 mg q.d., P < 0.0001; 600 mg b.i.d. versus 800 mg q.d., P = 0.447.

  • TABLE 4.

    Treatment-related adverse eventsa

    Event, body system, organ classNo. (%) of patients reporting
    Group 1 (200 mg q.i.d./ 400 mg b.i.d.) (n = 35)Group 2 (400 mg q.i.d./ 600 mg b.i.d.) (n = 31)Group 3 (800 mg b.i.d./ 800 mg q.d.) (n = 32)Total (n = 98)
    Total11 (31)6 (19)7 (22)24 (24)
    General disorders (headache, edema, rigors)3 (9)2 (6)2 (6)7 (7)
    Gastrointestinal system disorder7 (20)2 (6)b6 (19)15 (15)
        Diarrhea3 (3)01 (3)4 (4)
        Nausea4 (11)004 (4)
        Vomiting3 (9)03 (9)6 (6)
    Skin and subcutaneous tissue disorders (rash, pruritus, fissures)2 (6)1 (3)03 (3)
    • ↵ a All randomized patients reporting ≥2 events.

    • ↵ b Only one of these adverse events (abdominal pain) was considered by the investigator to be severe and possibly related to treatment.

  • TABLE 5.

    Treatment-emergent adverse events leading to study drug discontinuationa

    Event, body systemNo. (%) of patients reporting
    Group 1 (200 mg q.i.d./ 400 mg b.i.d.) (n = 35)Group 2 (400 mg q.i.d./ 600 mg b.i.d.) (n = 31)Group 3 (800 mg b.i.d./ 800 mg q.d.) (n = 32)Total (n = 98)
    Total8 (23)9 (29)7 (22)24 (24)
    General disorders (condition aggravated, fever, hypoxia, multiorgan failure)2 (6)2 (6)1 (3)5 (5)
    Central and peripheral nervous system disorder2 (6)1 (3)3 (9)6 (6)
    Gastrointestinal system disorder1 (3)2 (6)2 (6)5 (5)
    Infection (pneumonia, sepsis, septic shock, aspergillosis)1 (3)2 (6)1 (3)4 (4)
    Respiratory system disorders3 (9)2 (6)1 (3)6 (6)
    • ↵ a All randomized patients reporting ≥2 events.

  • TABLE 6.

    Clinical response at end of treatment in patients with rIFIs

    Clinical responseNo. (%) of patients
    Group 1 (200 mg q.i.d./400 mg b.i.d.)Group 2 (400 mg q.i.d./600 mg b.i.d.)Group 3 (800 mg b.i.d./800 mg q.d.)Total
    Efficacy evaluable (n = 9)All randomized (n = 12)Efficacy evaluable (n = 6)All randomized (n = 10)Efficacy evaluable (n = 6)All randomized (n = 10)Efficacy evaluable (n = 21)All randomized (n = 32)
    Responder (complete + partial)5 (56)6 (50)1 (17)1 (10)3 (50)4 (40)9 (43)11 (34)
        Complete00002 (33)3 (30)2 (10)3 (9)
        Partial5 (56)6 (50)1 (17)1 (10)1 (17)1 (10)7 (33)8 (25)
    Failure4 (44)6 (50)5 (83)9 (90)3 (50)6 (60)12 (57)21 (66)
        Stable disease1 (11)1 (8)1 (17)1 (10)1 (17)1 (10)3 (14)3 (9)
        Clinical failure3 (33)3 (25)2 (33)2 (20)1 (17)1 (10)6 (29)6 (19)
        Unable to determine001 (17)1 (10)1 (17)1 (10)2 (10)2 (6)
        Missing02 (17)1 (17)5 (50)03 (30)1 (5)10 (31)
  • TABLE 7.

    Clinical response at the end of treatment and 7 days after the end of treatment in patients with febrile neutropenia

    Efficacy outcomeNo. (%) of patients
    Group 1 (200 mg q.i.d./ 400 mg b.i.d.)Group 2 (400 mg q.i.d./ 600 mg b.i.d.)Group 3 (800 mg b.i.d./ 800 mg q.d.)Total
    Efficacy evaluableAll randomizedEfficacy evaluableAll randomizedEfficacy evaluableAll randomizedEfficacy evaluableAll randomized
    End of treatment
        Total1923182116225366
        Success14 (74)14 (61)14 (78)14 (67)13 (81)14 (64)41 (77)42 (64)
        Failure5 (26)9 (39)4 (23)7 (33)3 (19)8 (36)12 (23)24 (36)
            Clinical failure5 (26)6 (26)3 (17)4 (19)2 (13)2 (9)10 (19)12 (18)
            Missing03 (13)1 (6)3 (14)1 (6)6 (27)2 (4)12 (18)
    Posttreatment plus 7 daysa
        Total17171347
        Success13 (76)14 (82)11 (85)38 (81)
        Failure4 (24)3 (18)2 (15)9 (19)
            Clinical failure4 (24)2 (12)2 (15)8 (17)
            Missing01 (6)01 (2)
    • ↵ a Data for clinical efficacy 7 days after end of treatment were not collected for all randomized patients.

  • TABLE 8.

    Overall efficacy based on underlying factors (all randomized patients)

    Underlying factorFavorable outcome
    Persistent febrile neutropenia (n/total)Refractory disease (n[CR:PR]h/total)
    Efficacy evaluable (n = 53)All randomized (n = 66)Efficacy evaluable (n = 21)All randomized (n = 32)
    Underlying diseasea
        Leukemia32/3933/509[2:7]/2011[3:8]/32
        Non-Hodgkin's lymphoma6/76/80/10/1
        Myelodysplastic syndrome2/52/61[0:1]/31[0:1]/4
        Aplastic anemia2/32/40/00/0
        Other1/2b1/3c0/1d0/1d
    Transplantation history
        Allogeneic BMT5/76/92[1:1]/54[2:2]/12
            Unrelated4/55/71[0:1]/12[0:2]/4
            Related1/21/21[1:0]/42[2:0]/8
            Matched5/66/82[1:1]/54[2:2]/11
            Mismatched0/10/10/00/1
        Solid-organ transplant0/00/00/00/0
    Pathogen0/0e2/3f9[2:7]/2111[3:8]/32
        Aspergillus spp.0/01/12[1:1]/104[2:2]/17
        Fusarium spp.0/00/02[0:2]/22[0:2]/3
        Zygomycetes0/00/01[0:1]/31[0:1]/3
        Chromoblastomycosis0/00/01[1:0]/11[1:0]/1
        Othersg0/01/23[0:3]/53[0:3]/8
    Site of infection0/0e2/3f9[2:7]/2111[3:8]/32
        Pulmonary0/02/38[1:7]/209[2:7]/28
            Proven0/00/02[1:1]/42[0:2]/8
            Probable0/00/01[0:1]/92[1:1]/10
            Possible0/02/35[0:5]/75[1:4]/10
        Nonpulmonary0/00/01[0:1]/12[1:1]/4
            Sinus0/00/01[0:1]/11[0:1]/1
            Skin0/00/00/01[1:0]/1
            Blood0/00/00/00/1
            Oral0/00/00/00/1
    Neutropenic status41/5342/669[2:7]/2111[3:8]/32
        ANC ≤500 cells/μl involvement38/4939/601[0:1]/22[1:1]/3
        ANC >500 cells/μl2/32/38[2:6]/159[2:7]/21
        Missing1/11/30/40/8
    • ↵ a Patients could have had more than one underlying condition.

    • ↵ b Other underlying diseases were Hodgkin's disease (n = 1) and malignant testis neoplasm (n = 1).

    • ↵ c Other underlying diseases were Hodgkin's disease (n = 1), malignant testis neoplasm (n = 1), and neoplasm not otherwise specified (n = 1).

    • ↵ d Other underlying disease was malignant breast neoplasm (n = 1).

    • ↵ e One efficacy-evaluable patient had nonpulmonary (perianal) Geotrichum infection 3 days after posaconazole discontinuation and was not included in the analysis.

    • ↵ f Only three all-randomized patients had possible IFI during posaconazole treatment.

    • ↵ g Other pathogens were not specified.

    • ↵ h CR, complete response; PR, partial response.

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Pharmacokinetics, Safety, and Efficacy of Posaconazole in Patients with Persistent Febrile Neutropenia or Refractory Invasive Fungal Infection
A. J. Ullmann, O. A. Cornely, A. Burchardt, R. Hachem, D. P. Kontoyiannis, K. Töpelt, R. Courtney, D. Wexler, G. Krishna, M. Martinho, G. Corcoran, I. Raad
Antimicrobial Agents and Chemotherapy Jan 2006, 50 (2) 658-666; DOI: 10.1128/AAC.50.2.658-666.2006

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Pharmacokinetics, Safety, and Efficacy of Posaconazole in Patients with Persistent Febrile Neutropenia or Refractory Invasive Fungal Infection
A. J. Ullmann, O. A. Cornely, A. Burchardt, R. Hachem, D. P. Kontoyiannis, K. Töpelt, R. Courtney, D. Wexler, G. Krishna, M. Martinho, G. Corcoran, I. Raad
Antimicrobial Agents and Chemotherapy Jan 2006, 50 (2) 658-666; DOI: 10.1128/AAC.50.2.658-666.2006
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KEYWORDS

antifungal agents
Fever
Mycoses
neutropenia
triazoles

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