Article Figures & Data
Figures
- 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.
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
- TABLE 1.
Summary of patient demographic data
Characteristic Value 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 (%)] Female 14 (40) 14 (45) 10 (31) 38 (39) Male 21 (60) 17 (55) 22 (69) 60 (61) Race [n (%)] Caucasian 32 (91) 31 (100) 27 (84) 90 (92) Other 3 (9) 0 5 (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 FN 23 (66) 21 (68) 22 (69) 66 (67) rIFI 12 (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)a Value [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) 523 333 184 T max (h)b 3.0 (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)c 8,619 (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) - TABLE 4.
Treatment-related adverse eventsa
Event, body system, organ class No. (%) 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) Total 11 (31) 6 (19) 7 (22) 24 (24) General disorders (headache, edema, rigors) 3 (9) 2 (6) 2 (6) 7 (7) Gastrointestinal system disorder 7 (20) 2 (6)b 6 (19) 15 (15) Diarrhea 3 (3) 0 1 (3) 4 (4) Nausea 4 (11) 0 0 4 (4) Vomiting 3 (9) 0 3 (9) 6 (6) Skin and subcutaneous tissue disorders (rash, pruritus, fissures) 2 (6) 1 (3) 0 3 (3) - TABLE 5.
Treatment-emergent adverse events leading to study drug discontinuationa
Event, body system No. (%) 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) Total 8 (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 disorder 2 (6) 1 (3) 3 (9) 6 (6) Gastrointestinal system disorder 1 (3) 2 (6) 2 (6) 5 (5) Infection (pneumonia, sepsis, septic shock, aspergillosis) 1 (3) 2 (6) 1 (3) 4 (4) Respiratory system disorders 3 (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 response No. (%) 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) Complete 0 0 0 0 2 (33) 3 (30) 2 (10) 3 (9) Partial 5 (56) 6 (50) 1 (17) 1 (10) 1 (17) 1 (10) 7 (33) 8 (25) Failure 4 (44) 6 (50) 5 (83) 9 (90) 3 (50) 6 (60) 12 (57) 21 (66) Stable disease 1 (11) 1 (8) 1 (17) 1 (10) 1 (17) 1 (10) 3 (14) 3 (9) Clinical failure 3 (33) 3 (25) 2 (33) 2 (20) 1 (17) 1 (10) 6 (29) 6 (19) Unable to determine 0 0 1 (17) 1 (10) 1 (17) 1 (10) 2 (10) 2 (6) Missing 0 2 (17) 1 (17) 5 (50) 0 3 (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 outcome No. (%) 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 All randomized Efficacy evaluable All randomized Efficacy evaluable All randomized Efficacy evaluable All randomized End of treatment Total 19 23 18 21 16 22 53 66 Success 14 (74) 14 (61) 14 (78) 14 (67) 13 (81) 14 (64) 41 (77) 42 (64) Failure 5 (26) 9 (39) 4 (23) 7 (33) 3 (19) 8 (36) 12 (23) 24 (36) Clinical failure 5 (26) 6 (26) 3 (17) 4 (19) 2 (13) 2 (9) 10 (19) 12 (18) Missing 0 3 (13) 1 (6) 3 (14) 1 (6) 6 (27) 2 (4) 12 (18) Posttreatment plus 7 daysa Total 17 17 13 47 Success 13 (76) 14 (82) 11 (85) 38 (81) Failure 4 (24) 3 (18) 2 (15) 9 (19) Clinical failure 4 (24) 2 (12) 2 (15) 8 (17) Missing 0 1 (6) 0 1 (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 factor Favorable 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 Leukemia 32/39 33/50 9[2:7]/20 11[3:8]/32 Non-Hodgkin's lymphoma 6/7 6/8 0/1 0/1 Myelodysplastic syndrome 2/5 2/6 1[0:1]/3 1[0:1]/4 Aplastic anemia 2/3 2/4 0/0 0/0 Other 1/2b 1/3c 0/1d 0/1d Transplantation history Allogeneic BMT 5/7 6/9 2[1:1]/5 4[2:2]/12 Unrelated 4/5 5/7 1[0:1]/1 2[0:2]/4 Related 1/2 1/2 1[1:0]/4 2[2:0]/8 Matched 5/6 6/8 2[1:1]/5 4[2:2]/11 Mismatched 0/1 0/1 0/0 0/1 Solid-organ transplant 0/0 0/0 0/0 0/0 Pathogen 0/0e 2/3f 9[2:7]/21 11[3:8]/32 Aspergillus spp. 0/0 1/1 2[1:1]/10 4[2:2]/17 Fusarium spp. 0/0 0/0 2[0:2]/2 2[0:2]/3 Zygomycetes 0/0 0/0 1[0:1]/3 1[0:1]/3 Chromoblastomycosis 0/0 0/0 1[1:0]/1 1[1:0]/1 Othersg 0/0 1/2 3[0:3]/5 3[0:3]/8 Site of infection 0/0e 2/3f 9[2:7]/21 11[3:8]/32 Pulmonary 0/0 2/3 8[1:7]/20 9[2:7]/28 Proven 0/0 0/0 2[1:1]/4 2[0:2]/8 Probable 0/0 0/0 1[0:1]/9 2[1:1]/10 Possible 0/0 2/3 5[0:5]/7 5[1:4]/10 Nonpulmonary 0/0 0/0 1[0:1]/1 2[1:1]/4 Sinus 0/0 0/0 1[0:1]/1 1[0:1]/1 Skin 0/0 0/0 0/0 1[1:0]/1 Blood 0/0 0/0 0/0 0/1 Oral 0/0 0/0 0/0 0/1 Neutropenic status 41/53 42/66 9[2:7]/21 11[3:8]/32 ANC ≤500 cells/μl involvement 38/49 39/60 1[0:1]/2 2[1:1]/3 ANC >500 cells/μl 2/3 2/3 8[2:6]/15 9[2:7]/21 Missing 1/1 1/3 0/4 0/8 ↵ 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.
