- Email: [email protected]
Evaluation of the safety and efficacy of liposomal amphotericin B (L-AMB) in children
J Infect Chemother (2012) 18:456–465 DOI 10.1007/s10156-011-0357-4
ORIGINAL ARTICLE
Evaluation of the safety and efficacy of liposomal amphotericin B (L-AMB) in children Keisuke Sunakawa • Ichiro Tsukimoto • Yukiko Tsunematsu Masatada Honda • Naoichi Iwai • Takashi Maniwa • Hisamatsu Haigo • Kota Suzuki • Takeshi Mori
•
Received: 5 September 2011 / Accepted: 5 December 2011 / Published online: 31 January 2012 Ó Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2012
Abstract A multicenter, uncontrolled clinical study has been conducted to evaluate the safety, efficacy, and pharmacokinetics of liposomal amphotericin B (L-AMB) in children. In this article, the safety and efficacy of L-AMB are discussed. Subjects were diagnosed with invasive fungal infection (definitely diagnosed cases), possible fungal infection (clinically diagnosed cases), and febrile neutropenia with suspected fungal infection (febrile neutropenia cases). Of the 39 subjects treated with L-AMB, 18 received a definite (11) or clinical (7) diagnosis of invasive fungal infection. In these subjects, excluding one unevaluable subject, L-AMB was effective in nine out of 17 subjects (52.9%). Of 12 febrile neutropenia cases, improvement in
Naoichi Iwai: Deceased. K. Sunakawa Kitasato Institute for Life Science, Department of Research Project Studies, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-0072, Japan e-mail: [email protected] I. Tsukimoto Saiseikai Yokohamashi Tobu Hospital, 3-6-1 Shimosueyoshi, Tsurumi-ku, Yokohama 230-8765, Japan e-mail: [email protected] Y. Tsunematsu Hosen College of Childhood Education, 2-33-26 Chuo, Nakano-ku, Tokyo 164-8631, Japan e-mail: [email protected] M. Honda Tokyo Metropolitan Children’s Medical Center, Musashidai 2-8-29 Fuchu, Tokyo 183-8561, Japan e-mail: [email protected] N. Iwai Nagoya, Japan
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clinical symptoms, etc., was observed for six but these were excluded from the efficacy analysis because they concomitantly used medications that may have affected efficacy. The causative fungus was identified in four out of 39 subjects and confirmed to be eliminated by treatment with L-AMB in one subject. Adverse events possibly related to L-AMB (adverse drug reactions) were reported in 36 out of 39 subjects (92.3%). The most common adverse drug reaction was decreased potassium in 20 out of 39 subjects (51.3%), but all these subjects recovered with appropriate treatment, for example potassium supplementation. In a Japanese Phase II clinical study of adult patients, the incidence of adverse drug reactions was 95.3% (82/86 subjects) and the efficacy was 63.6% (42/66). Taken together, these data indicate that the safety and efficacy of L-AMB are almost the same in pediatric and adult patients. T. Maniwa H. Haigo Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan e-mail: [email protected] H. Haigo e-mail: [email protected] K. Suzuki (&) Dainippon Sumitomo Pharma Co., Ltd., 6-8 Doshomachi 2-Chome, Chuo-ku, Osaka 541-0045, Japan e-mail: [email protected] T. Mori Division of Hematology, Department of Internal Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo 113-8421, Japan e-mail: [email protected]
J Infect Chemother (2012) 18:456–465
Keywords Invasive fungal infection Children Liposomal amphotericin B Clinical study
Introduction Invasive fungal infection is a life-threatening infection in immunocompromised patients treated with hematopoietic stem cell transplantation or chemotherapy [1]. In children and adults, the occurrence of invasive fungal infection after treatment (i.e., bone marrow transplantation or chemotherapy) for blood disorders or malignancies poses a great problem [2–6]. Deoxycholate amphotericin B (D-AMB; FungizoneÒ; active ingredient, amphotericin B (AMPH-B)) has the broadest spectrum and the most potent antifungal activity of all antifungal agents. On the other hand, D-AMB cannot be used for long-term treatment because of serious adverse drug reactions, for example hypokalaemia or nephrotoxicity [7]. Alternatively, liposomal amphotericin B (L-AMB), which was developed to reduce the adverse drug reactions of AMPH-B without reducing its potent antifungal activity, is commonly used in clinical practice worldwide. In a UK double-blind comparative study of L-AMB versus D-AMB in neutropenia patients with pyrexia of unknown origin, L-AMB was as effective as D-AMB in children and adults, with a significantly lower overall incidence of adverse drug reactions, demonstrating the superiority of L-AMB [8]. In a European randomized double-blind comparative study of L-AMB versus the echinocandin antifungal agent caspofungin in children with febrile neutropenia, it was reported that L-AMB was as effective and safe as caspofungin [9]. In Japan, invasive fungal infection is primarily treated with systemic antifungal agents, including the polyene class of antifungal agents D-AMB and L-AMB, the echinocandin antifungal agent micafungin (MCFG), and azole antifungal agents fluconazole (FLCZ), fosfluconazole (F-FLCZ), itraconazole (ITCZ), voriconazole (VRCZ), and miconazole (MCZ), but only L-AMB and MCFG are approved for treatment of children. Other antifungal agents are therefore used for children on an off-label basis at dose levels in accordance with levels approved for adult patients. Thus, development of an antifungal agent for children is needed. An application in Japan to use L-AMB clinically was filed on the basis of the results of a Japanese clinical study of adult patients with invasive fungal infection, and the results of overseas clinical studies. It was approved in April 2006 for treatment of fungemia, respiratory mycosis, fungal meningitis, and disseminated mycosis caused by Aspergillus, Candida, and Cryptococcus and for the treatment of febrile neutropenia with suspected fungal infection, the first indication in Japan [10]. Its use for children was approved simultaneously with that for adult patients, on the basis of
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results from overseas clinical studies [8, 11] and on the basis of clinical experience in Japan, even though the Japanese clinical studies did not include children. A clinical study has therefore been conducted to further evaluate the safety, efficacy, and pharmacokinetics of L-AMB in Japanese children. The safety and efficacy results are reported below.
Patients and methods Diagnosis Invasive fungal infection was definitely diagnosed if the causative fungus was mycologically or histopathologically identified or the fungal strain was serologically identified (by antigen, antibody, and fungal genetic testing) and clinically diagnosed if the patient had clinical symptoms or image/endoscopic findings indicative of mycosis and was 1,3-b-D glucan-positive without mycological findings or fungal serologic findings. In addition, a case of febrile neutropenia with suspected fungal infection was defined as neutropenia in a patient who suffered from pyrexia after at least 3 days of antimicrobial treatment according to Infectious Diseases Society of America (IDSA) guidelines [12]. In clinically diagnosed cases and febrile neutropenia cases, efforts were made to establish a diagnosis even after the start of treatment with L-AMB. Inclusion criteria Primarily, definitely, or clinically diagnosed cases were enrolled in the study. Secondarily, febrile neutropenia cases were also enrolled because these patients are likely to develop fungal infection. In addition, subjects were inpatients aged between 28 days and 16 years. Written informed consent to participate in the study was obtained from each patient’s guardian, and consent was obtained from the patient, whenever possible, after explanation of the study. Exclusion criteria Patients were excluded from the study for the following reasons: responsiveness to treatment of the primary fungal infection episode (existing mycosis) with other antifungal agents; serious heart disease; history of hypersensitivity or allergy to AMPH-B; inappropriateness for entry into the study as judged by the investigator or subinvestigator. Dose and method of administration of the study drug For definitely or clinically diagnosed cases, L-AMB was administered at a dose of 2.5 mg/kg on day 1 of treatment.
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The dose could be increased (to 5.0 mg/kg, or to 6.0 mg/kg for cryptococcal meningitis), reduced (to 1.0 mg/kg), or discontinued on day 2 or any day thereafter. For febrile neutropenia cases, L-AMB was administered at a dose of 2.5 mg/kg on day 1 and could be administered at a reduced dose (down to 1.0 mg/kg) or suspended thereafter. Treatment was to be continued for up to 12 weeks until the success of treatment was achieved. Treatment could be suspended for up to 1 week. Prohibited concomitant medications Concomitant use of systemic antifungal agents, other investigational products, or drugs for post-marketing clinical studies was not allowed. In addition, leukocyte transfusion was prohibited because leukocyte transfusion in combination with AMPH-B can lead to acute impairment of pulmonary function [13]. Method of efficacy evaluation The primary efficacy endpoints were overall response and mycological response in patients in the efficacy population who had definitely or clinically diagnosed cases. Patients with a final diagnosis of febrile neutropenia cases were individually assessed for improvement in clinical symptoms and image/endoscopic findings, but not for the primary endpoints. In addition, unevaluable subjects were excluded from the efficacy evaluation. Overall efficacy was assessed on the basis of clinical symptoms and the results of imaging/endoscopy, mycological testing, and fungal serologic testing. Mycological efficacy was assessed only for patients whose mycological findings were positive at baseline. When a laboratory at the study site isolated and identified the causative fungus, the central laboratory identified this fungus again and determined the MIC of L-AMB and D-AMB. A committee of outside experts was organized to assess the validity of diagnosis and efficacy evaluation made by the investigator in a standardized manner.
Enrolled subjects: 41
Untreated subjects: 2
Treated subjects: 39
Cases excluded from the efficacy analysis population: 16
Definitely
Clinically diagnosed
Cases of febrile neutropenia with
diagnosed cases: 11
cases: 7
suspected fungal infection: 5
Fig. 1 Disposition of subjects
Results Disposition of subjects Disposition of subjects is shown in Fig. 1. Of 41 subjects enrolled, 39 subjects treated with L-AMB were included in the safety analysis population. Of the 39 subjects, 16 subjects were excluded from the efficacy analysis population for the following reasons: use of medications (e.g., G-CSF, etc.) that can affect evaluation of efficacy (n = 9), too short a duration of treatment (\7 days) to evaluate the efficacy (n = 3), and diagnosis of pneumocystis pneumonia (n = 2). Of the 23 subjects included in the efficacy analysis population, 11 were definitely diagnosed cases, seven were clinically diagnosed cases, and five were febrile neutropenia cases. Background of subjects Demographic and clinical background characteristics of 39 subjects treated with L-AMB are listed in Table 1. Many patients had severe underlying disease, for example leukemia or cancer, and 19 of 39 subjects had a history of hematopoietic stem cell transplantation. Thirty-seven subjects (94.9%) were unresponsive to other antifungal agents; the most common previously administered medications were micafungin and voriconazole.
Method of safety evaluation Efficacy evaluation Adverse events (including abnormal changes in laboratory values) reported during the treatment period and within 4 weeks after treatment were assessed by the investigator. For all adverse events, if the causal relationship to the investigational product could not be denied, such adverse events were regarded as ADRs. Because AMPH-B injection is known to cause pyrexia, chills, nausea, chest pain, back pain, reduced blood pressure, tachycardia, etc., all symptoms associated with infusion of the study drug were defined as infusion-related reactions and assessed.
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Overall efficacy Of the 23 subjects in the efficacy analysis population, 11 were definitely diagnosed cases, seven were clinically diagnosed cases, and five were febrile neutropenia cases. Treatment in the definitely or clinically diagnosed cases (n = 18) was effective in nine subjects, ineffective in eight subjects, and unevaluable in one subject (overall efficacy: 52.9%). In the one subject assessed as unevaluable, no fungal serologic efficacy against
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Table 1 Demographic and clinical background characteristics of subjects Definitely or clinically diagnosed casesa (N = 18)
Table 1 continued Safety analysis population (N = 39)
Definitely or clinically diagnosed casesa (N = 18)
Safety analysis population (N = 39) Underlying disease
Age Mean
7.9
AML
2
5
8.4
ALL
4
16
Standard deviation
4.5
4.5
Chronic granulomatosis
2
2
Minimum
1
0
Medulloblastoma
3
4
9.0
Neuroblastoma
2
2
MDS
0
1
Median Maximum
8.5 14
15
Mean
23.29
27.06
Standard deviation
11.83
14.11
7.8
6.1
Median
20.85
23.50
Micafungin injection
Maximum
46.9
63.8
Body weight
Minimum
3,525.73
2,069.59
Standard deviation
3,464.17
2,988.08
Minimum Median Maximum
0.0 2,679.00 12,788.0
0.0 600.00 12,788.0
Duration of treatment (day) Mean
22.9
14.2
Standard deviation
16.0
13.9
7
1
Median
19.5
11.0
Maximum
68
68
Minimum
Total dose (mg/body) Mean
1,453.18
934.74
Standard deviation
1,053.27
923.37
Minimum
254.8
10.4
Median
1,084.00
700.00
Maximum
3,998.4 11
23
7
16
Candidemia
5
6
Hepatosplenic candidiasis
1
1
Chronic necrotising pulmonary aspergillosis
1
1
Female
6
18
39
No
1
2
10
23
Voriconazole injection
8
11
Fluconazole injection
4
7
Other
9
29
AML acute myeloid leukemia, ALL acute lymphoblastic leukemia, MDS myelodysplastic syndromes, GVHD graft-versus-host disease a
Efficacy analysis population
b
Baseline value
c
Lung disorder, Ewing’s sarcoma, hyper IgG syndrome, etc.
fungi was found despite improvement in clinical symptoms. The overall efficacy by diagnosis of invasive fungal infection, treatment status, and body weight, and the background of the 17 subjects included in this evaluation are shown in Tables 2, 3, and 4. The evaluation of ‘‘effective’’ or ‘‘ineffective’’ was performed by the investigator. Mycological response
3,998.4
Sex Male
2
Otherc Prior medication for primary infection episode
Neutrophil countb Mean
GVHD
Diagnosis
Invasive pulmonary aspergillosis
3
4
Other aspergillosis
1
1
Pulmonary cryptococcosis
1
1
Other mycosis
6
13
Febrile neutropenia with suspected fungal infection
0
12
History of transplantation No
8
20
Yes
10
19
Before L-AMB treatment, seven organisms were isolated and identified from four of the 39 subjects (10.3%), including five strains of Candida parapsilosis in blood or catheter tip from three subjects and two isolates of C. tropicalis in sputum and feces from one subject. The minimum inhibitory concentrations (MIC) of L-AMB and D-AMB were, respectively, 2–4 and **0.5–1 lg/mL for C. parapsilosis and 2 and 0.5 lg/mL for C. tropicalis. For the four subjects from whom fungus was isolated, only one subject (25%) responded to L-AMB treatment, which completely eradicated the C. parapsilosis infection. Febrile neutropenia with suspected fungal infection (febrile neutropenia cases) Of the 39 subjects treated with L-AMB, 12 subjects were febrile neutropenia cases. Of the 12 subjects, five subjects
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460 Table 2 Efficacy in definitely or clinically diagnosed cases (overall efficacy)
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Diagnosis of invasive fungal infection
No. of subjects
Effective
Ineffective
Efficacy (%)
5
1
4
1/5 (20)
1
0
1
0/1 (0)
Definitely diagnosed cases Candidiasis Candidemia Aspergillosis Chronic necrotising pulmonary aspergillosis Invasive pulmonary aspergillosis
3
2
1
2/3 (66.7)
Other aspergillosis
1
1
0
1/1 (100)
1
1
0
1/1 (100)
Cryptococcosis Pulmonary cryptococcosis Clinically diagnosed cases
a
Unevaluable subjects were excluded
Table 3 Overall efficacy by treatment status and body weight
Hepatosplenic candidiasis
1
0
1
0/1 (0)
Other mycosis
5
4
1
4/5 (80)
17a
9
8
9/17 (52.9)
Total
Background
Number of subjects included in the evaluationa
Effective
Ineffective
Unevaluable
Efficacy (%)
Duration of treatment (days) 7–13
3
0
3
0
0
14–20
7
4
3
1
57.1
C21
7
5
2
0
71.4
The most common doseb 2.5 mg/kg
a
Excluding unevaluable subjects
b
Dose (2.5 or 5.0 mg/kg) used most frequently
11
6
5
1
54.5
5.0 mg/kg 6 Body weight (kg)
3
3
0
50.0 42.9
0–20
7
3
4
1
20–30
6
4
2
0
66.7
[30
4
2
2
0
50.0
were included in the efficacy analysis population, but improvement of clinical symptoms or image/endoscopic findings was not observed for any of this population. Safety evaluation Adverse events were reported in all of 39 subjects treated with L-AMB, including 36 subjects (92.3%) with adverse events possibly related to L-AMB (adverse drug reactions). Adverse drug reactions with an incidence of C5% are listed, with the number of affected subjects, in Table 5. Serious adverse events were reported for 16 of 39 subjects, including 11 subjects with 15 serious adverse drug reactions. Serious adverse drug reactions included hypokalaemia (n = 5), blood potassium decreased (n = 2), respiratory failure (n = 2), acute respiratory distress syndrome (n = 2), increased blood creatinine (n = 1), increased blood urea nitrogen (n = 1), muscular weakness (n = 1), and renal failure (n = 1). Of these reactions, hypokalaemia, blood
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potassium decreased, muscular weakness, and acute respiratory distress syndrome recovered with appropriate treatment. Fatal adverse events were reported for 6 (15.4%) of 39 subjects in the safety-analysis population. Of these events, adverse drug reactions were reported for two subjects (respiratory failure). For the other four subjects, the fatal event was considered by the investigator to be unrelated to L-AMB but rather to worsening of the underlying disease or complication. Twenty-four subjects (61.5%) were withdrawn from treatment with L-AMB. The main reasons were adverse drug reactions (n = 9), no response to L-AMB (n = 8), and noncompliance with the protocol because of transfer to another hospital, etc. (n = 3). Adverse drug reactions that led to withdrawal from treatment in nine subjects included hypokalaemia, increased blood creatinine, and acute respiratory distress syndrome (two subjects each). A total of 29 infusion-related reactions were reported for 11 of 39 subjects, but none was serious. The most common
11/M
8/F
10/M
12/M
13/F
4/M
6/M
1/M 9/F
9/M
14/F
13/M
2/M
7/M
1/M
6/F
14/F
1
2
3
4
5
6
7
8 9
10
11
12
13
14
15
16
17
Ewing’s sarcoma
ALL
Hyper IgM syndrome
Medulloblastoma
AML/aGVHD
ALL
Acute leukemia
Chronic granulomatosis
Lung disorder Neuroblastoma
Chronic granulomatosis
ALL
AML/GVHD
Neuroblastoma
Medulloblastoma
Brain tumor/MRSA infection
Adrenoleukodystrophy
Primary underlying disease
Fungal infection
Pulmonary mycosis
Suspected pulmonary mycosis
Respiratory mycosis
Suspected mycosis
Pulmonary cryptococcosis
Invasive pulmonary aspergillosis
Chronic necrotising pulmonary aspergillosis
Invasive pulmonary aspergillosis Other aspergillosis
Invasive pulmonary aspergillosis
Hepatosplenic candidiasis
Candidemia
Candidemia
Candidemia
Candidemia
Candidemia
Diagnosis of mycosis
b
a
Death due to an adverse drug reaction
Death due to worsening of the underlying disease or complication
s definitely diagnosed case, D clinically diagnosed case
Age/ sex
Patient no.
–
–
¯ –
–
–
–
–
– –
–
–
C. parapsilosis
C. parapsilosis
C. parapsilosis
C. tropicalis
–
Identified fungus
F-FLCZ/VRCZ ITCZ
s s
–
MCFG/ITCZ/VRCZ
s
D
MCFG VRCZ
s s
FLCZ/MCFG/VRCZ
ITCZ
s
ITCZ
MCFG
D
D
VRCZ
s
D
MCFG/F-FLCZ/VRCZ
s
MCFG
MCFG
s
MCFG/VRCZ
MCFG/VRCZ
s
D
F-FLCZ/VRCZ
s
D
Previous medication for primary fungal infection
Definitely/ clinically diagnosed case
Table 4 Background of 17 definitely or clinically diagnosed cases of invasive fungal infection (excluding unevaluable subjects)
26
68
28
21
57
27
14
17
7 14
18
20
7
20
14
28
8
Duration of treatment with L-AMB (days)
Effective
Effective
Ineffective
Effective
Effective
Effective
Effective
Ineffective
Ineffective Effective
Effective
Ineffective
Ineffective
Effective
Ineffective
Ineffective
Ineffective
Overall efficacy
Alive
Alive
Alive
Deada
Alive
Alive
Alive
Alive
Deada,b Deada,b
Alive
Alive
Deada
Alive
Deada
Alive
Alive
Outcome 28 days after completion of treatment
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Table 5 Adverse drug reactions with an incidence of C5% (including severe adverse drug reactions that occurred in at least 1 subject) System organ class
Preferred terma
Severity Mild
Total (%) N = 39 Moderate
Severe
4
14
2
20 (51.3)
2
1
0
3 (7.7)
All adverse drug reactions
36 (92.3)
Decreased potassiumb Cardiac disorders Gastrointestinal disorders General disorders and administration site conditions
Investigations
Arrhythmia Vomiting
8
0
0
8 (20.5)
Nausea
4
1
0
5 (12.8)
Malaise
4
0
0
4 (10.3)
Oedema Feeling hot
2 2
2 1
0 0
4 (10.3) 3 (7.7)
Pyrexia
2
1
0
3 (7.7)
Oedema peripheral
1
1
0
2 (5.1)
11
0
0
11 (28.2)
Blood potassium decreased
4
6
0
10 (25.6)
ALT increased
4
5
0
9 (23.1)
AST increased
4
5
0
9 (23.1)
Blood urea increased
7
1
1
9 (23.1)
Blood creatinine increased
3
4
1
8 (20.5)
Blood magnesium increased
5
0
0
5 (12.8)
GGTP increased
3
2
0
5 (12.8)
Blood cholesterol increased
4
0
0
4 (10.3)
Blood urine present
4
0
0
4 (10.3)
Blood lactate dehydrogenase increased
0
3
0
3 (7.7)
Blood magnesium decreased Blood triglycerides increased
2 3
1 0
0 0
3 (7.7) 3 (7.7)
Lipids increased
3
0
0
3 (7.7)
Beta 2 microglobulin increased
Urinary casts
3
0
0
3 (7.7)
Blood CPK increased
1
1
0
2 (5.1)
Blood pressure increased
2
0
0
2 (5.1)
Monocyte percentage decreased
2
0
0
2 (5.1)
Urine transitional cells present
2
0
0
2 (5.1)
Blood ALP increased
2
0
0
2 (5.1)
Urine output decreased
1
1
0
2 (5.1)
Hypokalaemia
0
8
2
10 (25.6)
Decreased appetite
2
0
0
2 (5.1)
Headache
3
0
0
3 (7.7)
Tremor
2
0
0
2 (5.1)
Renal failure
0
0
1
1 (2.6)
Proteinuria
2
0
0
2 (5.1)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome Respiratory failure
0 0
0 0
2 2
2 (5.1) 2 (5.1)
Vascular disorders
Flushing
2
2
0
4 (10.3)
Metabolism and nutrition disorders Nervous system disorders Renal and urinary disorders
ALT,alanine aminotransferase, AST aspartate aminotransferase, GGTP gamma-glutamyltransferase, CPK creatine phosphokinase, ALP alkaline phosphatase a
MedDRA Ver.12.1
b
Total number of subjects with hypokalaemia (blood potassium decreased)
infusion-related reactions were feeling hot, pyrexia, dyspnea, and flushing (three subjects each) and increased blood pressure (two subjects).
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The incidence of adverse drug reactions (i.e., abnormal serum creatinine, urea nitrogen, AST, and ALT levels) was high, and the time courses of these levels in all subjects are
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Fig. 2 a Time course of serum creatinine level. b Time course of urea nitrogen level. c Time course of AST (GOT) level. d Time course of ALT (GPT) level
shown in a–d of Fig. 2. Serum creatinine, urea nitrogen, AST, and ALT increased in some subjects, but levels in most subjects did not change. The dose for patients with increased serum creatinine level above 2.0 mg/dl and the dose for patients with urea nitrogen level above 70 mg/dl were both 2.5 mg/kg. The dose for patients with more than 50 days of L-AMB administration and elevated AST and ALT levels was 5.0 mg/kg, but a causal relationship between elevated AST and ALT, and L-AMB was ruled out because of complications.
Discussion In Japan, L-AMB is already approved for treatment of children, yet no data are available from Japanese clinical studies of children. Therefore, this study was conducted to evaluate the safety and efficacy of L-AMB in Japanese children. For 17 of the 39 pediatric subjects for whom efficacy for invasive fungal infection could be assessed, the efficacy was 52.9% (9/17 subjects) which was similar to the efficacy of 63.6% (42/66 subjects) in a Japanese Phase II clinical study of adult patients [10].
Of 39 subjects treated with L-AMB, 37 subjects (94.9%) had previously been treated with, and been unresponsive to, other antifungal agents. All 37 subjects were then treated with L-AMB and enrolled in this study. In previously unresponsive subjects for whom efficacy could be assessed, efficacy was 50.0% (8/16 subjects). The efficacy for subjects with each previous antifungal agent treatment was 25% (1/4) for MCFG alone, 50% (1/2) for VRCZ alone, 50% (1/2) for VRCZ ? MCFG, 50% (1/2) for VRCZ plus FLCZ or F-FLCZ, 66.7% (2/3) for VRCZ ? MCFG ? another azole, and 66.7% (2/3) for ITCZ alone, showing that L-AMB was effective for patients unresponsive to echinocandin or azole antifungal agents. Even if the presence of fungus could not be confirmed by culture, direct microscopy, etc., 1,3-b-D glucan-positive patients who had fungal infection diagnosed by clinical symptoms or characteristic image findings were enrolled in this study as patients with suspected fungal infection (clinically diagnosed cases).The efficacy in the clinically diagnosed cases was 66.7% (4/6), and tended to be higher than the efficacy in the definitely diagnosed cases (45.5%; 5/11). As in another study, which showed that when fungal infection is suspected, earlier antifungal treatment results
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in higher efficacy, results of this study also seem to support the importance of early treatment [14]. Of the efficacyassessable subjects, all nine responsive subjects (and five of eight unresponsive subjects) had decreased potassium. As shown in Table 3, longer duration of treatment tended to result in greater efficacy, suggesting that both appropriate treatment of decreased potassium and continuous treatment with L-AMB are important to achievement of efficacy. For some subjects the dose was reduced to 1.0 mg/kg, but the dose used more frequently was 2.5 or 5.0 mg/kg. Dependence of efficacy on dose was almost the same. Efficacy against fungal infection (although the sample size was small) was 60% (3/5) for aspergillosis, 100% (1/1) for cryptococcosis, and 80% (4/5) in the clinically diagnosed cases, compared with 16.7% (1/6) for candidiasis. The efficacy rate for candidiasis was low for several reasons. First, the fungus was isolated and identified in blood, etc., from four of 39 subjects treated with L-AMB at baseline, and all four subjects suffered from severe candidiasis at the point of entry into the study (efficacy 25%; 1/4). Second, all five candidiasis subjects unresponsive to L-AMB were also unresponsive to previous treatment with MCFG or VRCZ, and four subjects (excluding one subject withdrawn because of an adverse event) were withdrawn from treatment because of no response to L-AMB, indicating that the candidiasis in these five subjects was not responsive to different classes of antifungal agents and could not be managed with monotherapy. Third, two of five candidiasis subjects unresponsive to L-AMB died within 30 days after withdrawal from treatment with L-AMB, because of worsening of the underlying disease or complication (only one subject with noncandidal infection died because of worsening of the complication), suggesting that their very poor general condition at baseline left little room for improvement. In summary, subjects with candidiasis (compared with subjects with noncandidal mycoses) were less responsive because the disease at entry was already more severe and therefore more refractory to treatment. Of 12 subjects finally diagnosed with febrile neutropenia with suspected fungal infection, five subjects were included in the efficacy evaluation, but improvement in clinical symptoms, etc., was not observed for any subject. On the other hand, six of seven subjects excluded from the evaluation achieved improvement in clinical symptoms (for example pyrexia) and imaging/endoscopic findings. However, all six subjects concomitantly used medications that may have affected the efficacy and were thus excluded from the evaluation, because it could not be determined whether L-AMB definitely contributed to improvement in clinical symptoms, etc. Adverse events were reported for all 39 subjects treated with L-AMB, including adverse drug reactions for 36 (92.3%) subjects. Adverse drug reactions were reported for
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most subjects in this study, just as they were in a previous study of Japanese adult patients (82/86, 95.3%) [10]. AMPH-B may reduce blood potassium by damaging the renal tubules [15–19]. In this study, the most common adverse drug reaction was reduced blood potassium (hypokalaemia or blood potassium decreased) in 20 (51.3%) of 39 subjects, but all these subjects recovered with appropriate treatment, for example potassium supplementation. Because a serious decrease in potassium may cause arrhythmia, general malaise, feelings of weakness, etc., it may be necessary to monitor the potassium concentration closely. Invasive fungal infection or febrile neutropenia with suspected fungal infection are often associated with severe underlying diseases, for example malignancy, leukemia, graft-versus-host disease, etc., that involve chemotherapy, radiotherapy, or bone marrow transplantation, and are more likely to have a fatal outcome. In this study, four of the six deaths were because of worsening of underlying diseases or complications and considered by the investigator to be unrelated to treatment with L-AMB. Two cases of respiratory failure reported as an adverse drug reaction may have been associated with not only L-AMB but also the underlying disease and/or other concomitant medications. The causal relationship with L-AMB is thus unclear. The pharmacokinetic results from this study will be reported elsewhere. In conclusion, this study of Japanese children showed that adverse drug reactions occurred in nearly all children treated with L-AMB at the approved dose, as they did in adult patients. However, the main adverse reaction was reduced potassium, and appropriate treatment, for example potassium supplementation, usually eliminated this reaction, as it did in adult patients. The efficacy for our 39 subjects treated with L-AMB, 37 of whom were unresponsive to previous treatment with other antifungal agents, was almost to the same as that for Japanese adult patients, demonstrating that L-AMB is useful for treatment of children also. This is especially important because invasive fungal infection and febrile neutropenia are fatal diseases. Acknowledgments The authors are grateful to the following investigators: Ryoji Kobayashi, Tadashi Ariga, Makoto Kaneda, Hokkaido University Hospital; Kiminori Terui, Hirosaki University School of Medicine & Hospital; Shigeru Tsuchiya, Tohoku University Hospital; Keiko Asami, Niigata Cancer Center Hospital; Atsushi Kikuta, Fukushima Medical University Hospital; Masahiro Tsuchida, Ibaraki Children’s Hospital; Akira Kikuchi, Shinji Mochizuki, Saitama Children’s Medical Center; Atushi Makimoto, National Cancer Center Hospital; Hiroaki Goto, Yokohama City University Hospital; Hisato Kigasawa, Kanagawa Children’s Medical Center; Yasuo Horikoshi, Shizuoka Children’s Hospital; Yutaka Saikawa, Ryosei Nishimura, Kanazawa University Hospital; Koji Kato, Japanese Red Cross Nagoya Daiichi Hospital; Hiroshi Yagasaki, Yoshiyuki Takahashi, Nagoya University Hospital; Tatsutoshi Nakahata, Kenichiro Watanabe, Kyoto University Hospital; Junichi Hara, Osaka City
J Infect Chemother (2012) 18:456–465 General Hospital; Keisei Kawa, Masami Inoue, Osaka Medical Center and Research Institute for Maternal and Child Health; Kosuke Chayama, Okayama University Hospital of Medicine and Dentistry; Masao Kobayashi, Hiroshima University Hospital; Tsutomu Watanabe, Hiroyoshi Watanabe, Tokushima University Hospital; Yoshihisa Nagatoshi, National Hospital Organization Kyushu Cancer Center; Yoshifumi Kawano, Kagoshima University Medical and Dental Hospital; Arata Watanabe, Meiwakai Nakadori General Hospital; Shosuke Sunami, Narita Red Cross Hospital; Takashi Kaneko, Tokyo Metropolitan Kiyose Children’s Hospital; Masahiro Saito, Juntendo University Hospital; Yoshiyuki Kosaka, Hyogo Prefectural Kobe Children’s Hospital; Akitoshi Kinoshita, St. Marianna University Hospital; Keizo Horibe, National Hospital Organization Nagoya Medical Center; Hajime Hosoi, Tomoko Iehara, University Hospital, Kyoto Prefectural University of Medicine; Tsunekazu Haruta, Kobe City Medical Center General Hospital; Takayuki Okamura, Satoru Hamada, University Hospital, University of the Ryukyus; Shinichi Kobayashi, National Center for Child Health and Development; Hiroko Inada, Kurume University Hospital.
References 1. Sipsas NV, Bodey GP, Kontoyiannis DP. Perspectives for the management of febrile neutropenic patients with cancer in the 21st century. Cancer. 2005;103:1103–13. 2. Ridola V, Chachaty E, Raimondo G, Corradini N, Brugieres L, Valteau-Couanet D, et al. Candida infections in children treated with conventional chemotherapy for solid tumors (transplant recipients excluded): the Institute Gustave Roussy Pediatrics Department experience. Pediatr Blood Cancer. 2004;42:332–7. 3. Groll AH, Kurz M, Schneider W, Witt V, Schmidt H, Schneider M, et al. Five-year-survey of invasive aspergillosis in a paediatric cancer centre. Epidemiology, management and long-term survival. Mycoses. 1999;42:431–42. 4. Hovi L, Saarinen-Pihkala UM, Vettenranta K, Saxen H. Invasive fungal infections in pediatric bone marrow transplant recipients: single center experience of 10 years. Bone Marrow Transpl. 2000;26:999–1004. 5. Krupova Y, Sejnova D, Dzatkova J, Kaiserova E, Kiskova M, Babela R, et al. Prospective study on fungemia in children with cancer: analysis of 35 cases and comparison with 130 fungemias in adults. Support Care Cancer. 2000;8:427–30. 6. Castagnola E, Cesaro S, Giacchino M, Livadiotti S, Tucci F, Zanazzo G, et al. Fungal infections in children with cancer a prospective, multicenter surveillance study. Pediatr Infect Dis J. 2006;25:634–9. 7. Hoeprich PD. Clinical use of amphotericin B and derivatives: lore, mystique, and fact. Clin Infect Dis. 1992;14(Suppl 1): s114–9.
465 8. Prentice HG, Hann IM, Herbrecht R, Aoun M, Kvaloy S, Catovsky D, et al. A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients. Br J Haematol. 1997;98(3):711–8. 9. Maertens JA, Madero L, Reilly AF, Lehrnbecher T, Groll AH, Jafri HS, et al. A randomized, double-blind, multicenter study of caspofungin versus liposomal amphotericin B for empiric antifungal therapy in pediatric patients with persistent fever and neutropenia. Pediatr Infect Dis J. 2010;29:415–20. 10. Maniwa T, Yamamoto Y. Antifungal activity and clinical efficacy of liposomal amphotericin B (AmBisome). Folia Pharmakol Jpn. 2007;129:129–34. 11. Walsh TJ, Finberg RW, Arndt C, Hiemenz J, Schwartz C, Bodensteiner D, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. N Engl J Med. 1999;340:764–71. 12. Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis. 2002;34:730–51. 13. Wright DG, Robichaud KJ, Pizzo PA, Deisseroth AB. Lethal pulmonary reactions associated with the combined use of amphotericin B and leukocyte transfusions. N Engl J Med. 1981;304:1185–9. 14. Kolve H, Ahlke E, Fegeler W, Ritter J, Ju¨rgens H, Groll AH. Safety, tolerance and outcome of treatment with liposomal amphotericin B in paediatric patients with cancer or undergoing haematopoietic stem cell transplantation. J Antimicrob Chemother. 2009;64:383–7. 15. Reiner NE, Thompson WL. Dopamine and saralasin antagonism of renal vasoconstriction and oliguria caused by amphotericin B in dogs. J Infect Dis. 1979;140:564–75. 16. Gerkens JF, Heidemann HT, Jackson EK, Branch RA. Effect of aminophylline on amphotericin B nephrotoxicity in the dog. J Pharmacol Exp Ther. 1983;224:609–13. 17. Nichols AJ, Koster PF, Brooks DP, Ruffolo RR Jr. Effect of fenoldpam on the acute and subacute nephrotoxicity produced by amphotericin B in the dog. J Pharmacol Exp Ther. 1992;260: 269–74. 18. Gerkens JF, Branch RA. The influence of sodium status and furosemide on canine acute amphotericin B nephrotoxicity. J Pharmacol Exp Ther. 1980;214:306–11. 19. Tasset C, Preat V, Bernard A, Roland M. Comparison of nephrotoxicities of different polyoxyethyleneglycol formulations of amphotericin B in rats. Antimicrob Agents Chemother. 1992;36: 1525–31.
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ORIGINAL ARTICLE
Evaluation of the safety and efficacy of liposomal amphotericin B (L-AMB) in children Keisuke Sunakawa • Ichiro Tsukimoto • Yukiko Tsunematsu Masatada Honda • Naoichi Iwai • Takashi Maniwa • Hisamatsu Haigo • Kota Suzuki • Takeshi Mori
•
Received: 5 September 2011 / Accepted: 5 December 2011 / Published online: 31 January 2012 Ó Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2012
Abstract A multicenter, uncontrolled clinical study has been conducted to evaluate the safety, efficacy, and pharmacokinetics of liposomal amphotericin B (L-AMB) in children. In this article, the safety and efficacy of L-AMB are discussed. Subjects were diagnosed with invasive fungal infection (definitely diagnosed cases), possible fungal infection (clinically diagnosed cases), and febrile neutropenia with suspected fungal infection (febrile neutropenia cases). Of the 39 subjects treated with L-AMB, 18 received a definite (11) or clinical (7) diagnosis of invasive fungal infection. In these subjects, excluding one unevaluable subject, L-AMB was effective in nine out of 17 subjects (52.9%). Of 12 febrile neutropenia cases, improvement in
Naoichi Iwai: Deceased. K. Sunakawa Kitasato Institute for Life Science, Department of Research Project Studies, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-0072, Japan e-mail: [email protected] I. Tsukimoto Saiseikai Yokohamashi Tobu Hospital, 3-6-1 Shimosueyoshi, Tsurumi-ku, Yokohama 230-8765, Japan e-mail: [email protected] Y. Tsunematsu Hosen College of Childhood Education, 2-33-26 Chuo, Nakano-ku, Tokyo 164-8631, Japan e-mail: [email protected] M. Honda Tokyo Metropolitan Children’s Medical Center, Musashidai 2-8-29 Fuchu, Tokyo 183-8561, Japan e-mail: [email protected] N. Iwai Nagoya, Japan
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clinical symptoms, etc., was observed for six but these were excluded from the efficacy analysis because they concomitantly used medications that may have affected efficacy. The causative fungus was identified in four out of 39 subjects and confirmed to be eliminated by treatment with L-AMB in one subject. Adverse events possibly related to L-AMB (adverse drug reactions) were reported in 36 out of 39 subjects (92.3%). The most common adverse drug reaction was decreased potassium in 20 out of 39 subjects (51.3%), but all these subjects recovered with appropriate treatment, for example potassium supplementation. In a Japanese Phase II clinical study of adult patients, the incidence of adverse drug reactions was 95.3% (82/86 subjects) and the efficacy was 63.6% (42/66). Taken together, these data indicate that the safety and efficacy of L-AMB are almost the same in pediatric and adult patients. T. Maniwa H. Haigo Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan e-mail: [email protected] H. Haigo e-mail: [email protected] K. Suzuki (&) Dainippon Sumitomo Pharma Co., Ltd., 6-8 Doshomachi 2-Chome, Chuo-ku, Osaka 541-0045, Japan e-mail: [email protected] T. Mori Division of Hematology, Department of Internal Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo 113-8421, Japan e-mail: [email protected]
J Infect Chemother (2012) 18:456–465
Keywords Invasive fungal infection Children Liposomal amphotericin B Clinical study
Introduction Invasive fungal infection is a life-threatening infection in immunocompromised patients treated with hematopoietic stem cell transplantation or chemotherapy [1]. In children and adults, the occurrence of invasive fungal infection after treatment (i.e., bone marrow transplantation or chemotherapy) for blood disorders or malignancies poses a great problem [2–6]. Deoxycholate amphotericin B (D-AMB; FungizoneÒ; active ingredient, amphotericin B (AMPH-B)) has the broadest spectrum and the most potent antifungal activity of all antifungal agents. On the other hand, D-AMB cannot be used for long-term treatment because of serious adverse drug reactions, for example hypokalaemia or nephrotoxicity [7]. Alternatively, liposomal amphotericin B (L-AMB), which was developed to reduce the adverse drug reactions of AMPH-B without reducing its potent antifungal activity, is commonly used in clinical practice worldwide. In a UK double-blind comparative study of L-AMB versus D-AMB in neutropenia patients with pyrexia of unknown origin, L-AMB was as effective as D-AMB in children and adults, with a significantly lower overall incidence of adverse drug reactions, demonstrating the superiority of L-AMB [8]. In a European randomized double-blind comparative study of L-AMB versus the echinocandin antifungal agent caspofungin in children with febrile neutropenia, it was reported that L-AMB was as effective and safe as caspofungin [9]. In Japan, invasive fungal infection is primarily treated with systemic antifungal agents, including the polyene class of antifungal agents D-AMB and L-AMB, the echinocandin antifungal agent micafungin (MCFG), and azole antifungal agents fluconazole (FLCZ), fosfluconazole (F-FLCZ), itraconazole (ITCZ), voriconazole (VRCZ), and miconazole (MCZ), but only L-AMB and MCFG are approved for treatment of children. Other antifungal agents are therefore used for children on an off-label basis at dose levels in accordance with levels approved for adult patients. Thus, development of an antifungal agent for children is needed. An application in Japan to use L-AMB clinically was filed on the basis of the results of a Japanese clinical study of adult patients with invasive fungal infection, and the results of overseas clinical studies. It was approved in April 2006 for treatment of fungemia, respiratory mycosis, fungal meningitis, and disseminated mycosis caused by Aspergillus, Candida, and Cryptococcus and for the treatment of febrile neutropenia with suspected fungal infection, the first indication in Japan [10]. Its use for children was approved simultaneously with that for adult patients, on the basis of
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results from overseas clinical studies [8, 11] and on the basis of clinical experience in Japan, even though the Japanese clinical studies did not include children. A clinical study has therefore been conducted to further evaluate the safety, efficacy, and pharmacokinetics of L-AMB in Japanese children. The safety and efficacy results are reported below.
Patients and methods Diagnosis Invasive fungal infection was definitely diagnosed if the causative fungus was mycologically or histopathologically identified or the fungal strain was serologically identified (by antigen, antibody, and fungal genetic testing) and clinically diagnosed if the patient had clinical symptoms or image/endoscopic findings indicative of mycosis and was 1,3-b-D glucan-positive without mycological findings or fungal serologic findings. In addition, a case of febrile neutropenia with suspected fungal infection was defined as neutropenia in a patient who suffered from pyrexia after at least 3 days of antimicrobial treatment according to Infectious Diseases Society of America (IDSA) guidelines [12]. In clinically diagnosed cases and febrile neutropenia cases, efforts were made to establish a diagnosis even after the start of treatment with L-AMB. Inclusion criteria Primarily, definitely, or clinically diagnosed cases were enrolled in the study. Secondarily, febrile neutropenia cases were also enrolled because these patients are likely to develop fungal infection. In addition, subjects were inpatients aged between 28 days and 16 years. Written informed consent to participate in the study was obtained from each patient’s guardian, and consent was obtained from the patient, whenever possible, after explanation of the study. Exclusion criteria Patients were excluded from the study for the following reasons: responsiveness to treatment of the primary fungal infection episode (existing mycosis) with other antifungal agents; serious heart disease; history of hypersensitivity or allergy to AMPH-B; inappropriateness for entry into the study as judged by the investigator or subinvestigator. Dose and method of administration of the study drug For definitely or clinically diagnosed cases, L-AMB was administered at a dose of 2.5 mg/kg on day 1 of treatment.
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The dose could be increased (to 5.0 mg/kg, or to 6.0 mg/kg for cryptococcal meningitis), reduced (to 1.0 mg/kg), or discontinued on day 2 or any day thereafter. For febrile neutropenia cases, L-AMB was administered at a dose of 2.5 mg/kg on day 1 and could be administered at a reduced dose (down to 1.0 mg/kg) or suspended thereafter. Treatment was to be continued for up to 12 weeks until the success of treatment was achieved. Treatment could be suspended for up to 1 week. Prohibited concomitant medications Concomitant use of systemic antifungal agents, other investigational products, or drugs for post-marketing clinical studies was not allowed. In addition, leukocyte transfusion was prohibited because leukocyte transfusion in combination with AMPH-B can lead to acute impairment of pulmonary function [13]. Method of efficacy evaluation The primary efficacy endpoints were overall response and mycological response in patients in the efficacy population who had definitely or clinically diagnosed cases. Patients with a final diagnosis of febrile neutropenia cases were individually assessed for improvement in clinical symptoms and image/endoscopic findings, but not for the primary endpoints. In addition, unevaluable subjects were excluded from the efficacy evaluation. Overall efficacy was assessed on the basis of clinical symptoms and the results of imaging/endoscopy, mycological testing, and fungal serologic testing. Mycological efficacy was assessed only for patients whose mycological findings were positive at baseline. When a laboratory at the study site isolated and identified the causative fungus, the central laboratory identified this fungus again and determined the MIC of L-AMB and D-AMB. A committee of outside experts was organized to assess the validity of diagnosis and efficacy evaluation made by the investigator in a standardized manner.
Enrolled subjects: 41
Untreated subjects: 2
Treated subjects: 39
Cases excluded from the efficacy analysis population: 16
Definitely
Clinically diagnosed
Cases of febrile neutropenia with
diagnosed cases: 11
cases: 7
suspected fungal infection: 5
Fig. 1 Disposition of subjects
Results Disposition of subjects Disposition of subjects is shown in Fig. 1. Of 41 subjects enrolled, 39 subjects treated with L-AMB were included in the safety analysis population. Of the 39 subjects, 16 subjects were excluded from the efficacy analysis population for the following reasons: use of medications (e.g., G-CSF, etc.) that can affect evaluation of efficacy (n = 9), too short a duration of treatment (\7 days) to evaluate the efficacy (n = 3), and diagnosis of pneumocystis pneumonia (n = 2). Of the 23 subjects included in the efficacy analysis population, 11 were definitely diagnosed cases, seven were clinically diagnosed cases, and five were febrile neutropenia cases. Background of subjects Demographic and clinical background characteristics of 39 subjects treated with L-AMB are listed in Table 1. Many patients had severe underlying disease, for example leukemia or cancer, and 19 of 39 subjects had a history of hematopoietic stem cell transplantation. Thirty-seven subjects (94.9%) were unresponsive to other antifungal agents; the most common previously administered medications were micafungin and voriconazole.
Method of safety evaluation Efficacy evaluation Adverse events (including abnormal changes in laboratory values) reported during the treatment period and within 4 weeks after treatment were assessed by the investigator. For all adverse events, if the causal relationship to the investigational product could not be denied, such adverse events were regarded as ADRs. Because AMPH-B injection is known to cause pyrexia, chills, nausea, chest pain, back pain, reduced blood pressure, tachycardia, etc., all symptoms associated with infusion of the study drug were defined as infusion-related reactions and assessed.
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Overall efficacy Of the 23 subjects in the efficacy analysis population, 11 were definitely diagnosed cases, seven were clinically diagnosed cases, and five were febrile neutropenia cases. Treatment in the definitely or clinically diagnosed cases (n = 18) was effective in nine subjects, ineffective in eight subjects, and unevaluable in one subject (overall efficacy: 52.9%). In the one subject assessed as unevaluable, no fungal serologic efficacy against
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Table 1 Demographic and clinical background characteristics of subjects Definitely or clinically diagnosed casesa (N = 18)
Table 1 continued Safety analysis population (N = 39)
Definitely or clinically diagnosed casesa (N = 18)
Safety analysis population (N = 39) Underlying disease
Age Mean
7.9
AML
2
5
8.4
ALL
4
16
Standard deviation
4.5
4.5
Chronic granulomatosis
2
2
Minimum
1
0
Medulloblastoma
3
4
9.0
Neuroblastoma
2
2
MDS
0
1
Median Maximum
8.5 14
15
Mean
23.29
27.06
Standard deviation
11.83
14.11
7.8
6.1
Median
20.85
23.50
Micafungin injection
Maximum
46.9
63.8
Body weight
Minimum
3,525.73
2,069.59
Standard deviation
3,464.17
2,988.08
Minimum Median Maximum
0.0 2,679.00 12,788.0
0.0 600.00 12,788.0
Duration of treatment (day) Mean
22.9
14.2
Standard deviation
16.0
13.9
7
1
Median
19.5
11.0
Maximum
68
68
Minimum
Total dose (mg/body) Mean
1,453.18
934.74
Standard deviation
1,053.27
923.37
Minimum
254.8
10.4
Median
1,084.00
700.00
Maximum
3,998.4 11
23
7
16
Candidemia
5
6
Hepatosplenic candidiasis
1
1
Chronic necrotising pulmonary aspergillosis
1
1
Female
6
18
39
No
1
2
10
23
Voriconazole injection
8
11
Fluconazole injection
4
7
Other
9
29
AML acute myeloid leukemia, ALL acute lymphoblastic leukemia, MDS myelodysplastic syndromes, GVHD graft-versus-host disease a
Efficacy analysis population
b
Baseline value
c
Lung disorder, Ewing’s sarcoma, hyper IgG syndrome, etc.
fungi was found despite improvement in clinical symptoms. The overall efficacy by diagnosis of invasive fungal infection, treatment status, and body weight, and the background of the 17 subjects included in this evaluation are shown in Tables 2, 3, and 4. The evaluation of ‘‘effective’’ or ‘‘ineffective’’ was performed by the investigator. Mycological response
3,998.4
Sex Male
2
Otherc Prior medication for primary infection episode
Neutrophil countb Mean
GVHD
Diagnosis
Invasive pulmonary aspergillosis
3
4
Other aspergillosis
1
1
Pulmonary cryptococcosis
1
1
Other mycosis
6
13
Febrile neutropenia with suspected fungal infection
0
12
History of transplantation No
8
20
Yes
10
19
Before L-AMB treatment, seven organisms were isolated and identified from four of the 39 subjects (10.3%), including five strains of Candida parapsilosis in blood or catheter tip from three subjects and two isolates of C. tropicalis in sputum and feces from one subject. The minimum inhibitory concentrations (MIC) of L-AMB and D-AMB were, respectively, 2–4 and **0.5–1 lg/mL for C. parapsilosis and 2 and 0.5 lg/mL for C. tropicalis. For the four subjects from whom fungus was isolated, only one subject (25%) responded to L-AMB treatment, which completely eradicated the C. parapsilosis infection. Febrile neutropenia with suspected fungal infection (febrile neutropenia cases) Of the 39 subjects treated with L-AMB, 12 subjects were febrile neutropenia cases. Of the 12 subjects, five subjects
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460 Table 2 Efficacy in definitely or clinically diagnosed cases (overall efficacy)
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Diagnosis of invasive fungal infection
No. of subjects
Effective
Ineffective
Efficacy (%)
5
1
4
1/5 (20)
1
0
1
0/1 (0)
Definitely diagnosed cases Candidiasis Candidemia Aspergillosis Chronic necrotising pulmonary aspergillosis Invasive pulmonary aspergillosis
3
2
1
2/3 (66.7)
Other aspergillosis
1
1
0
1/1 (100)
1
1
0
1/1 (100)
Cryptococcosis Pulmonary cryptococcosis Clinically diagnosed cases
a
Unevaluable subjects were excluded
Table 3 Overall efficacy by treatment status and body weight
Hepatosplenic candidiasis
1
0
1
0/1 (0)
Other mycosis
5
4
1
4/5 (80)
17a
9
8
9/17 (52.9)
Total
Background
Number of subjects included in the evaluationa
Effective
Ineffective
Unevaluable
Efficacy (%)
Duration of treatment (days) 7–13
3
0
3
0
0
14–20
7
4
3
1
57.1
C21
7
5
2
0
71.4
The most common doseb 2.5 mg/kg
a
Excluding unevaluable subjects
b
Dose (2.5 or 5.0 mg/kg) used most frequently
11
6
5
1
54.5
5.0 mg/kg 6 Body weight (kg)
3
3
0
50.0 42.9
0–20
7
3
4
1
20–30
6
4
2
0
66.7
[30
4
2
2
0
50.0
were included in the efficacy analysis population, but improvement of clinical symptoms or image/endoscopic findings was not observed for any of this population. Safety evaluation Adverse events were reported in all of 39 subjects treated with L-AMB, including 36 subjects (92.3%) with adverse events possibly related to L-AMB (adverse drug reactions). Adverse drug reactions with an incidence of C5% are listed, with the number of affected subjects, in Table 5. Serious adverse events were reported for 16 of 39 subjects, including 11 subjects with 15 serious adverse drug reactions. Serious adverse drug reactions included hypokalaemia (n = 5), blood potassium decreased (n = 2), respiratory failure (n = 2), acute respiratory distress syndrome (n = 2), increased blood creatinine (n = 1), increased blood urea nitrogen (n = 1), muscular weakness (n = 1), and renal failure (n = 1). Of these reactions, hypokalaemia, blood
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potassium decreased, muscular weakness, and acute respiratory distress syndrome recovered with appropriate treatment. Fatal adverse events were reported for 6 (15.4%) of 39 subjects in the safety-analysis population. Of these events, adverse drug reactions were reported for two subjects (respiratory failure). For the other four subjects, the fatal event was considered by the investigator to be unrelated to L-AMB but rather to worsening of the underlying disease or complication. Twenty-four subjects (61.5%) were withdrawn from treatment with L-AMB. The main reasons were adverse drug reactions (n = 9), no response to L-AMB (n = 8), and noncompliance with the protocol because of transfer to another hospital, etc. (n = 3). Adverse drug reactions that led to withdrawal from treatment in nine subjects included hypokalaemia, increased blood creatinine, and acute respiratory distress syndrome (two subjects each). A total of 29 infusion-related reactions were reported for 11 of 39 subjects, but none was serious. The most common
11/M
8/F
10/M
12/M
13/F
4/M
6/M
1/M 9/F
9/M
14/F
13/M
2/M
7/M
1/M
6/F
14/F
1
2
3
4
5
6
7
8 9
10
11
12
13
14
15
16
17
Ewing’s sarcoma
ALL
Hyper IgM syndrome
Medulloblastoma
AML/aGVHD
ALL
Acute leukemia
Chronic granulomatosis
Lung disorder Neuroblastoma
Chronic granulomatosis
ALL
AML/GVHD
Neuroblastoma
Medulloblastoma
Brain tumor/MRSA infection
Adrenoleukodystrophy
Primary underlying disease
Fungal infection
Pulmonary mycosis
Suspected pulmonary mycosis
Respiratory mycosis
Suspected mycosis
Pulmonary cryptococcosis
Invasive pulmonary aspergillosis
Chronic necrotising pulmonary aspergillosis
Invasive pulmonary aspergillosis Other aspergillosis
Invasive pulmonary aspergillosis
Hepatosplenic candidiasis
Candidemia
Candidemia
Candidemia
Candidemia
Candidemia
Diagnosis of mycosis
b
a
Death due to an adverse drug reaction
Death due to worsening of the underlying disease or complication
s definitely diagnosed case, D clinically diagnosed case
Age/ sex
Patient no.
–
–
¯ –
–
–
–
–
– –
–
–
C. parapsilosis
C. parapsilosis
C. parapsilosis
C. tropicalis
–
Identified fungus
F-FLCZ/VRCZ ITCZ
s s
–
MCFG/ITCZ/VRCZ
s
D
MCFG VRCZ
s s
FLCZ/MCFG/VRCZ
ITCZ
s
ITCZ
MCFG
D
D
VRCZ
s
D
MCFG/F-FLCZ/VRCZ
s
MCFG
MCFG
s
MCFG/VRCZ
MCFG/VRCZ
s
D
F-FLCZ/VRCZ
s
D
Previous medication for primary fungal infection
Definitely/ clinically diagnosed case
Table 4 Background of 17 definitely or clinically diagnosed cases of invasive fungal infection (excluding unevaluable subjects)
26
68
28
21
57
27
14
17
7 14
18
20
7
20
14
28
8
Duration of treatment with L-AMB (days)
Effective
Effective
Ineffective
Effective
Effective
Effective
Effective
Ineffective
Ineffective Effective
Effective
Ineffective
Ineffective
Effective
Ineffective
Ineffective
Ineffective
Overall efficacy
Alive
Alive
Alive
Deada
Alive
Alive
Alive
Alive
Deada,b Deada,b
Alive
Alive
Deada
Alive
Deada
Alive
Alive
Outcome 28 days after completion of treatment
J Infect Chemother (2012) 18:456–465 461
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462
J Infect Chemother (2012) 18:456–465
Table 5 Adverse drug reactions with an incidence of C5% (including severe adverse drug reactions that occurred in at least 1 subject) System organ class
Preferred terma
Severity Mild
Total (%) N = 39 Moderate
Severe
4
14
2
20 (51.3)
2
1
0
3 (7.7)
All adverse drug reactions
36 (92.3)
Decreased potassiumb Cardiac disorders Gastrointestinal disorders General disorders and administration site conditions
Investigations
Arrhythmia Vomiting
8
0
0
8 (20.5)
Nausea
4
1
0
5 (12.8)
Malaise
4
0
0
4 (10.3)
Oedema Feeling hot
2 2
2 1
0 0
4 (10.3) 3 (7.7)
Pyrexia
2
1
0
3 (7.7)
Oedema peripheral
1
1
0
2 (5.1)
11
0
0
11 (28.2)
Blood potassium decreased
4
6
0
10 (25.6)
ALT increased
4
5
0
9 (23.1)
AST increased
4
5
0
9 (23.1)
Blood urea increased
7
1
1
9 (23.1)
Blood creatinine increased
3
4
1
8 (20.5)
Blood magnesium increased
5
0
0
5 (12.8)
GGTP increased
3
2
0
5 (12.8)
Blood cholesterol increased
4
0
0
4 (10.3)
Blood urine present
4
0
0
4 (10.3)
Blood lactate dehydrogenase increased
0
3
0
3 (7.7)
Blood magnesium decreased Blood triglycerides increased
2 3
1 0
0 0
3 (7.7) 3 (7.7)
Lipids increased
3
0
0
3 (7.7)
Beta 2 microglobulin increased
Urinary casts
3
0
0
3 (7.7)
Blood CPK increased
1
1
0
2 (5.1)
Blood pressure increased
2
0
0
2 (5.1)
Monocyte percentage decreased
2
0
0
2 (5.1)
Urine transitional cells present
2
0
0
2 (5.1)
Blood ALP increased
2
0
0
2 (5.1)
Urine output decreased
1
1
0
2 (5.1)
Hypokalaemia
0
8
2
10 (25.6)
Decreased appetite
2
0
0
2 (5.1)
Headache
3
0
0
3 (7.7)
Tremor
2
0
0
2 (5.1)
Renal failure
0
0
1
1 (2.6)
Proteinuria
2
0
0
2 (5.1)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome Respiratory failure
0 0
0 0
2 2
2 (5.1) 2 (5.1)
Vascular disorders
Flushing
2
2
0
4 (10.3)
Metabolism and nutrition disorders Nervous system disorders Renal and urinary disorders
ALT,alanine aminotransferase, AST aspartate aminotransferase, GGTP gamma-glutamyltransferase, CPK creatine phosphokinase, ALP alkaline phosphatase a
MedDRA Ver.12.1
b
Total number of subjects with hypokalaemia (blood potassium decreased)
infusion-related reactions were feeling hot, pyrexia, dyspnea, and flushing (three subjects each) and increased blood pressure (two subjects).
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The incidence of adverse drug reactions (i.e., abnormal serum creatinine, urea nitrogen, AST, and ALT levels) was high, and the time courses of these levels in all subjects are
J Infect Chemother (2012) 18:456–465
463
Fig. 2 a Time course of serum creatinine level. b Time course of urea nitrogen level. c Time course of AST (GOT) level. d Time course of ALT (GPT) level
shown in a–d of Fig. 2. Serum creatinine, urea nitrogen, AST, and ALT increased in some subjects, but levels in most subjects did not change. The dose for patients with increased serum creatinine level above 2.0 mg/dl and the dose for patients with urea nitrogen level above 70 mg/dl were both 2.5 mg/kg. The dose for patients with more than 50 days of L-AMB administration and elevated AST and ALT levels was 5.0 mg/kg, but a causal relationship between elevated AST and ALT, and L-AMB was ruled out because of complications.
Discussion In Japan, L-AMB is already approved for treatment of children, yet no data are available from Japanese clinical studies of children. Therefore, this study was conducted to evaluate the safety and efficacy of L-AMB in Japanese children. For 17 of the 39 pediatric subjects for whom efficacy for invasive fungal infection could be assessed, the efficacy was 52.9% (9/17 subjects) which was similar to the efficacy of 63.6% (42/66 subjects) in a Japanese Phase II clinical study of adult patients [10].
Of 39 subjects treated with L-AMB, 37 subjects (94.9%) had previously been treated with, and been unresponsive to, other antifungal agents. All 37 subjects were then treated with L-AMB and enrolled in this study. In previously unresponsive subjects for whom efficacy could be assessed, efficacy was 50.0% (8/16 subjects). The efficacy for subjects with each previous antifungal agent treatment was 25% (1/4) for MCFG alone, 50% (1/2) for VRCZ alone, 50% (1/2) for VRCZ ? MCFG, 50% (1/2) for VRCZ plus FLCZ or F-FLCZ, 66.7% (2/3) for VRCZ ? MCFG ? another azole, and 66.7% (2/3) for ITCZ alone, showing that L-AMB was effective for patients unresponsive to echinocandin or azole antifungal agents. Even if the presence of fungus could not be confirmed by culture, direct microscopy, etc., 1,3-b-D glucan-positive patients who had fungal infection diagnosed by clinical symptoms or characteristic image findings were enrolled in this study as patients with suspected fungal infection (clinically diagnosed cases).The efficacy in the clinically diagnosed cases was 66.7% (4/6), and tended to be higher than the efficacy in the definitely diagnosed cases (45.5%; 5/11). As in another study, which showed that when fungal infection is suspected, earlier antifungal treatment results
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in higher efficacy, results of this study also seem to support the importance of early treatment [14]. Of the efficacyassessable subjects, all nine responsive subjects (and five of eight unresponsive subjects) had decreased potassium. As shown in Table 3, longer duration of treatment tended to result in greater efficacy, suggesting that both appropriate treatment of decreased potassium and continuous treatment with L-AMB are important to achievement of efficacy. For some subjects the dose was reduced to 1.0 mg/kg, but the dose used more frequently was 2.5 or 5.0 mg/kg. Dependence of efficacy on dose was almost the same. Efficacy against fungal infection (although the sample size was small) was 60% (3/5) for aspergillosis, 100% (1/1) for cryptococcosis, and 80% (4/5) in the clinically diagnosed cases, compared with 16.7% (1/6) for candidiasis. The efficacy rate for candidiasis was low for several reasons. First, the fungus was isolated and identified in blood, etc., from four of 39 subjects treated with L-AMB at baseline, and all four subjects suffered from severe candidiasis at the point of entry into the study (efficacy 25%; 1/4). Second, all five candidiasis subjects unresponsive to L-AMB were also unresponsive to previous treatment with MCFG or VRCZ, and four subjects (excluding one subject withdrawn because of an adverse event) were withdrawn from treatment because of no response to L-AMB, indicating that the candidiasis in these five subjects was not responsive to different classes of antifungal agents and could not be managed with monotherapy. Third, two of five candidiasis subjects unresponsive to L-AMB died within 30 days after withdrawal from treatment with L-AMB, because of worsening of the underlying disease or complication (only one subject with noncandidal infection died because of worsening of the complication), suggesting that their very poor general condition at baseline left little room for improvement. In summary, subjects with candidiasis (compared with subjects with noncandidal mycoses) were less responsive because the disease at entry was already more severe and therefore more refractory to treatment. Of 12 subjects finally diagnosed with febrile neutropenia with suspected fungal infection, five subjects were included in the efficacy evaluation, but improvement in clinical symptoms, etc., was not observed for any subject. On the other hand, six of seven subjects excluded from the evaluation achieved improvement in clinical symptoms (for example pyrexia) and imaging/endoscopic findings. However, all six subjects concomitantly used medications that may have affected the efficacy and were thus excluded from the evaluation, because it could not be determined whether L-AMB definitely contributed to improvement in clinical symptoms, etc. Adverse events were reported for all 39 subjects treated with L-AMB, including adverse drug reactions for 36 (92.3%) subjects. Adverse drug reactions were reported for
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most subjects in this study, just as they were in a previous study of Japanese adult patients (82/86, 95.3%) [10]. AMPH-B may reduce blood potassium by damaging the renal tubules [15–19]. In this study, the most common adverse drug reaction was reduced blood potassium (hypokalaemia or blood potassium decreased) in 20 (51.3%) of 39 subjects, but all these subjects recovered with appropriate treatment, for example potassium supplementation. Because a serious decrease in potassium may cause arrhythmia, general malaise, feelings of weakness, etc., it may be necessary to monitor the potassium concentration closely. Invasive fungal infection or febrile neutropenia with suspected fungal infection are often associated with severe underlying diseases, for example malignancy, leukemia, graft-versus-host disease, etc., that involve chemotherapy, radiotherapy, or bone marrow transplantation, and are more likely to have a fatal outcome. In this study, four of the six deaths were because of worsening of underlying diseases or complications and considered by the investigator to be unrelated to treatment with L-AMB. Two cases of respiratory failure reported as an adverse drug reaction may have been associated with not only L-AMB but also the underlying disease and/or other concomitant medications. The causal relationship with L-AMB is thus unclear. The pharmacokinetic results from this study will be reported elsewhere. In conclusion, this study of Japanese children showed that adverse drug reactions occurred in nearly all children treated with L-AMB at the approved dose, as they did in adult patients. However, the main adverse reaction was reduced potassium, and appropriate treatment, for example potassium supplementation, usually eliminated this reaction, as it did in adult patients. The efficacy for our 39 subjects treated with L-AMB, 37 of whom were unresponsive to previous treatment with other antifungal agents, was almost to the same as that for Japanese adult patients, demonstrating that L-AMB is useful for treatment of children also. This is especially important because invasive fungal infection and febrile neutropenia are fatal diseases. Acknowledgments The authors are grateful to the following investigators: Ryoji Kobayashi, Tadashi Ariga, Makoto Kaneda, Hokkaido University Hospital; Kiminori Terui, Hirosaki University School of Medicine & Hospital; Shigeru Tsuchiya, Tohoku University Hospital; Keiko Asami, Niigata Cancer Center Hospital; Atsushi Kikuta, Fukushima Medical University Hospital; Masahiro Tsuchida, Ibaraki Children’s Hospital; Akira Kikuchi, Shinji Mochizuki, Saitama Children’s Medical Center; Atushi Makimoto, National Cancer Center Hospital; Hiroaki Goto, Yokohama City University Hospital; Hisato Kigasawa, Kanagawa Children’s Medical Center; Yasuo Horikoshi, Shizuoka Children’s Hospital; Yutaka Saikawa, Ryosei Nishimura, Kanazawa University Hospital; Koji Kato, Japanese Red Cross Nagoya Daiichi Hospital; Hiroshi Yagasaki, Yoshiyuki Takahashi, Nagoya University Hospital; Tatsutoshi Nakahata, Kenichiro Watanabe, Kyoto University Hospital; Junichi Hara, Osaka City
J Infect Chemother (2012) 18:456–465 General Hospital; Keisei Kawa, Masami Inoue, Osaka Medical Center and Research Institute for Maternal and Child Health; Kosuke Chayama, Okayama University Hospital of Medicine and Dentistry; Masao Kobayashi, Hiroshima University Hospital; Tsutomu Watanabe, Hiroyoshi Watanabe, Tokushima University Hospital; Yoshihisa Nagatoshi, National Hospital Organization Kyushu Cancer Center; Yoshifumi Kawano, Kagoshima University Medical and Dental Hospital; Arata Watanabe, Meiwakai Nakadori General Hospital; Shosuke Sunami, Narita Red Cross Hospital; Takashi Kaneko, Tokyo Metropolitan Kiyose Children’s Hospital; Masahiro Saito, Juntendo University Hospital; Yoshiyuki Kosaka, Hyogo Prefectural Kobe Children’s Hospital; Akitoshi Kinoshita, St. Marianna University Hospital; Keizo Horibe, National Hospital Organization Nagoya Medical Center; Hajime Hosoi, Tomoko Iehara, University Hospital, Kyoto Prefectural University of Medicine; Tsunekazu Haruta, Kobe City Medical Center General Hospital; Takayuki Okamura, Satoru Hamada, University Hospital, University of the Ryukyus; Shinichi Kobayashi, National Center for Child Health and Development; Hiroko Inada, Kurume University Hospital.
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