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Micafungin

A Review of its Use in the Prophylaxis and Treatment of Invasive Candida Infections in Pediatric Patients

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Summary

Abstract

Intravenous micafungin (Mycamine®; Funguard®) is an echinocandin indicated in Japan and the EU for the treatment of pediatric patients (including neonates) with invasive candidiasis and as prophylaxis against Candida infection in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). In the EU, micafungin is also indicated in pediatric patients who are expected to have neutropenia for ≥10 days. In Japan, children may also receive micafungin for the treatment of, or as prophylaxis against, invasive Aspergillus infection. Micafungin is not currently approved for use in pediatric patients in the US.

Micafungin has very good antifungal activity against a wide range of Candida spp. in vitro. It has a favorable pharmacokinetic profile allowing for once-daily administration, has few drug-drug interactions, and reports of resistance are rare. The results of pediatric substudies indicate that intravenous micafungin is effective in a majority of patients for the treatment of candidemia and other types of invasive candidiasis, and provides effective prophylaxis against invasive fungal infections in pediatric patients undergoing HSCT. The tolerability profile of micafungin in pediatric patients was generally acceptable. In the EU, micafungin is indicated for use when other antifungal medications are not appropriate. Therefore, micafungin provides an alternative to other antifungal agents used in the management of candidemia and invasive candidiasis in pediatric patients, or as prophylaxis against fungal infections in pediatric patients undergoing HSCT.

Pharmacologic Properties

Micafungin inhibits the synthesis of 1,3-β-D-glucan, a major component of fungal cell walls. It has demonstrated in vitro antifungal and fungicidal activity against a wide range of Candida spp. encountered clinically, including multidrug-resistant Candida spp. residing in biofilms, and fluconazole-resistant Candida spp. In two large (n >1000 clinical isolates) studies, the minimum inhibitory concentration at which 90% of isolates were inhibited (MIC90) was 0.015–0.06 μg/mL for C. albicans, C. glabrata, C. kefyr, and C. tropicalis isolates. In the larger of the two studies, the micafungin MIC90 was 0.015–2 μg/mL across all Candida spp. isolates, and 100% susceptibility to micafungin was seen at an MIC of 0.06–2 μg/mL, depending on the isolate. An MIC susceptibility breakpoint for micafungin against Candida spp. of ≤2μg/mL was recently established by the Clinical and Laboratory Standards Institute. Reports of resistance to micafungin are rare.

Because of its high molecular weight, micafungin has poor oral bioavailability and is only available for intravenous administration. Over a dose range of 0.5–6.0 mg/kg, micafungin demonstrated linear, dose-proportional pharmacokinetics in pediatric patients with febrile neutropenia or deep mycosis and in premature neonates with a variety of underlying conditions. Micafungin is >99% plasma protein bound. It is mainly metabolized in the liver and is predominantly excreted via the fecal route. The clearance of micafungin was affected by age, with patients aged 2–8 years clearing the drug more quickly than those aged 9–17 years. Micafungin had few drug-drug interactions.

Therapeutic Efficacy

Intravenous micafungin was effective in the treatment of pediatric patients aged <16 years (including neonates) with candidemia or other types of invasive candidiasis in a pediatric substudy (n= 109) of a large (n = 537), randomized, double-blind, multicenter, phase III trial. In this substudy, the efficacy of micafungin 2 mg/kg/day in patients weighing ≤40 kg and 100 mg/day in those weighing >40 kg was compared with that of liposomal amphotericin B 3 mg/kg/day; all medications were infused over 1 hour each day for 2–8 weeks. Candidemia accounted for over 90% of infections in this study, and a non-C. albicans spp. was the infecting organism in ≈60% of cases. Micafungin was effective in the majority of patients for the treatment of candidemia or other types of invasive candidiasis, irrespective of patient age, primary diagnosis, baseline neutropenic status, and whether or not the patient required an increase in drug dosage, was born prematurely, or had an intravenous catheter present at baseline. With regard to the primary endpoint, 73% and 76% of micafungin and liposomal amphotericin B recipients achieved treatment success (i.e. clinical and mycologic response) at the end of treatment (EOT) as determined by the study investigator. Mycologic persistence at EOT occurred in 16% of patients in each treatment arm. Three patients in the micafungin group and no patients in the liposomal amphotericin B group had confirmed recurrence of fungal infection during the 12-week, post-treatment follow-up period.

Micafungin was also effective in the majority of patients as prophylaxis against invasive fungal infections in a subgroup of neutropenic pediatric patients (n = 84) undergoing HSCT who were included in a large (n = 882), randomized, double-blind, multicenter, phase III trial. Patients in this trial received micafungin 1 mg/kg/day (or 50 mg/day depending on patient weight) or intravenous fluconazole 8 mg/kg/day (or 400 mg/day depending on patient weight) over 1 hour for a mean duration of 23 days. In pediatric patients, treatment success (i.e. absence of systemic fungal infection; primary endpoint) occurred in 69% of micafungin recipients and 53% of fluconazole recipients. During the trial, one micafungin recipient and three fluconazole recipients developed proven or probable breakthrough infections.

Tolerability

The tolerability profile of micafungin was generally acceptable in pediatric patients with complex and life-threatening illnesses who received the drug for the treatment of invasive candidiasis or aspergillosis, or as prophylaxis against these infections. In addition, micafungin up to a dosage of 10 mg/kg/day appeared to be generally well tolerated in healthy neonates (n= 13). Data from a pediatric substudy (n= 106) also suggest that micafungin has a generally similar tolerability profile to that of liposomal amphotericin B in pediatric patients with candidemia or other types of invasive candidiasis.

The incidences of the most common adverse events associated with micafungin (i.e. infusion reactions, fever, and hypokalemia) were not significantly different from those reported with liposomal amphotericin B in the pediatric substudy. In a pooled analysis of data from pediatric patients in several clinical trials (n = 296), the most frequently occurring treatment-related adverse events were hypokalemia, increases in AST, ALT, bilirubin, or alkaline phosphatase levels, abnormal liver function tests, and hypertension. Elevations in creatinine, AST, ALT, and/or bilirubin from normal at baseline to above the upper limit of normal (ULN) or >2 or >2.5 × the ULN occurred in <25% of micafungin recipients and <20% of liposomal amphotericin B recipients in the pediatric substudy and ≥10% of micafungin recipients in the pooled analysis. Serious treatment-related adverse events occurred in 4% and 9% of patients in the pediatric substudy who received micafungin or liposomal amphotericin B. The rate of treatment discontinuations due to a treatment-related adverse event was 2% and 6% in micafungin and liposomal amphotericin B recipients. Seven treatment discontinuations occurred as a result of treatment-related adverse events associated with micafungin in the pooled analysis, and two of these were as a result of serious treatment-related adverse events.

Micafungin has been associated with isolated cases of more severe hepatic dysfunction, hepatitis, and hepatic failure. Pediatric patients appear more likely than adults to develop micafungin-associated liver function test abnormalities, and those aged <1 year are more likely to be affected than older pediatric patients. This may reflect the higher proportion of serious underlying disorders in the younger pediatric patients compared with the older children or adults.

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Authors and Affiliations

  1. Wolters Kluwer Health / Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand

    Natalie J. Carter & Gillian M. Keating

  2. Wolters Kluwer Health, Philadelphia, Pennsylvania, USA

    Natalie J. Carter & Gillian M. Keating

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  1. Natalie J. Carter
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  2. Gillian M. Keating
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Correspondence to Natalie J. Carter.

Additional information

Various sections of the manuscript reviewed by: I.W. Fong, Division of Infectious Diseases, University of Toronto, Toronto, Ontario, Canada; A.H. Groll, Center for Bone Marrow Transplantation and Department of Pediatric Hematology and Oncology, University Children’s Hospital, Muenster, Germany; P. Palasanthiran, Department of Immunology and Infectious Diseases, Sydney Children’s Hospital, Randwick, New South Wales, Australia; T. Rogers, Department of Clinical Microbiology, Trinity College Dublin, Dublin, Ireland; A. Shetty, Department of Medical Microbiology, Cwm Taf NHS Trust, Wales, UK.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘micafungin’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health ∣ Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE, and AdisBase search terms were ‘micafungin’ and (‘children’ or ‘infant’ or ‘neonatal’ or ‘pediatric’ or ‘paediatric’). Searches were last updated 18 June 2009.

Selection: Studies in patients with candidemia or invasive candidiasis who received micafungin. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Micafungin, candidemia, invasive candidiasis, candida, adolescents, children, infants, neonates, pediatric, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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Carter, N.J., Keating, G.M. Micafungin. Pediatr-Drugs 11, 271–291 (2009). https://doi.org/10.2165/00148581-200911040-00006

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