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Micafungin in a Nutshell: State of Affairs on the Pharmacological and Clinical Aspects of the Novel Echinocandin

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Micafungin in a Nutshell: State of Affairs on the Pharmacological and Clinical Aspects of the Novel Echinocandin Drug Evaluation Micafungin in a nutshell: state of affairs on the pharmacological and clinical aspects of the novel echinocandin Micafungin is one of three echinocandin antifungals approved by the US FDA and the European Medicines Agency (EMA). Like all echinocandin antifungals, micafungin inhibits the synthesis of 1,3‑b‑d‑glucan, a main component of the cell wall of many medically important fungi; thus, exerting fungicidal activity against most Candida spp., as well as fungistatic activity against many Aspergillus spp. Micafungin displays linear pharmacokinetics over the therapeutic range with a long half‑life, allowing once‑daily intravenous administration. Steady state serum concentrations are achieved after 3 days. Since therapeutic concentrations of micafungin are achieved after the administration of a standard dose there is no need for a loading dose. Interactions of micafungin with the cytochrome P450 (CYP3A4) system are marginal; and, consequently, no severe drug–drug interactions have been reported so far. Furthermore, micafungin exhibited favorable profiles for tolerability and safety; no dose‑limiting toxicity has been established yet. However, despite its favorable characteristics, these are no unique features among the echinocandins. Nevertheless, micafungin is the only echinocandin that has been approved for the prophylaxis of Candida spp. infections in patients undergoing hematopoietic stem cell transplantation. KEywords: antifungal agents n aspergillosis n candidiasis n dose–response Fedja Farowski†1, relationship n drug administration schedule n drug interactions n lipoproteins Jörg J Vehreschild2, n mycoses n peptides Oliver A Cornely1,3 & Maria JGT Vehreschild1 The incidence of invasive fungal diseases (IFDs) patients with febrile neutropenia (FN), treat- 1Klinikum der Universität zu Köln, has increased, mainly owing to the growing num- ment of esophageal candidiasis, candidemia Klinik I für Innere Medizin, 50924 Köln, ber of immunocompromised patients in recent and other spp. infections, as well as the Germany Candida 2Klinikum der Universität zu Köln, years. The most common pathogens of IFDs in treatment of IA in patients who are refractory Klinik I für Innere Medizin the immunocompromised host are Candida spp. or intolerant to other therapies [101]. Micafungin (BMBF 01KI0771), 50924 Köln, Germany and Aspergillus spp. Infections caused by Candida has been approved by the European Medicines 3Universität zu Köln, Zentrum für spp. account for 8–10% of all nosocomial blood- Agency (EMA) in April 2008 and the FDA in Klinische Studien (ZKS Köln, BMBF 01KN0706), 50924 Köln, stream infections in US hospitals [1]. Despite March 2005 for the treatment of patients with Germany new antifungal therapies, the attributable mor- esophageal candidiasis, invasive candidiasis and †Author for correspondence: tality rate of up to 49% remains unacceptably the prophylaxis of infections in patients Uniklinik Köln, Klinik I für Innere Candida Medizin, Klinisches Studienzentrum 2 high [2]. The emergence of infections caused by undergoing hematopoietic stem cell transplanta- für Infektiologie, Kerpener Straße 62 Candida spp. other than Candida albicans has tion (HSCT) [101,102]. Anidulafungin is the lat- 50937 Köln, Germany Tel.: +49 221 478 6494 been repeatedly reported [1,3]. est antifungal agent of this class and has been Fax: +49 221 478 3611 Aspergillus spp. are ubiquitous soil-dwelling approved by the FDA for the treatment of esoph- [email protected] fungi that may cause life-threatening IFD in ageal candidiasis, candidemia and other Candida immunocompromised patients. The most com- spp. infections [103]. The EMA approved anidu- mon (80–90%) form of invasive aspergillosis lafungin for the treatment of invasive candidiasis (IA) is invasive pulmonary aspergillosis. in adult non-neutropenic patients [104]. Echinocandin class Micafungin Echinocandin antifungals are a recent addition Micafungin is derived from the water-soluble to the antifungal armamentarium. They target echinocandin-like fermentation product (lipo- the fungal cell wall by inhibiting the production peptide FR901379) of Coleophoma empetri of 1,3-b-d‑glucan. Currently, three antifungals F-11889, by replacement of the lipophilic side of the echinocandin class are commercially avail- chain, which results in a reduced hemolytic able. The first echinocandin to gain approval potential [101]. from the US FDA was caspofungin. Approval The chemical designation of mica fungin was granted for the following indications: empiri- sodium is pneumocandin A0, 1-[(4R,5R) cal treatment of presumed fungal infections in -4,5-dihydroxy-N2-[4-[5-[4-(pentyloxy) 10.2217/THY.10.45 © 2010 Future Medicine Ltd Therapy (2010) 7(5), 555–563 ISSN 1475-0708 555 Drug Evaluation Farowski, Vehreschild, Cornely & Vehreschild Micafungin in a nutshell: pharmacological & clinical aspects Drug Evaluation phenyl]-3-isoxazolyl]benzoyl]-l-ornithine]-4 other Candida spp. [7]. No significant changes -[(4S)-4-hydroxy-4-[4-hydroxy-3-(sulfooxy) in the activity against strains of Candida were phenyl]-l‑threonine], monosodium salt, with noticed during the 6-year study period from an empirical formula of C56H70N9NaO23S and January 2001 to December 2006 [8]. Resistance a molecular weight of 1292.26 g/mol (Figure 1). to micafungin may be caused by mutations within highly conserved regions of the FSK1, Mode of action and, to a lesser extent, FSK2 genes, which encode Micafungin acts as a noncompetitive inhibitor for certain subunits of the 1,3-b-d‑glucan syn- of 1,3-b‑d‑glucan synthesis; hence, inhibiting thase [9]. However, recent results from a large the production of a main component of the and geographically diverse Candida spp. col- cell wall in many medically important fungi. lection (n = 133) demonstrated that mutations Consequently, the fungal cell walls become of the FSK1 gene remain uncommon among less stable and unable to resist osmotic pres- isolates with various MIC levels [10]. sure, which ultimately leads to cell lysis. It has Micafungin also demonstrated good in vitro been demonstrated that even low concentra- antifungal activity against clinical isolates of tions of micafungin result in a marked effect Aspergillus flavus (n = 18), Aspergillus fumigatus on the cell wall, in other words, morphological (n = 35), Aspergillus nidulans (n = 3), Aspergillus changes and occasional cell lysis, of Candida niger (n = 20), Aspergillus terreus (n = 12) and albicans [4,5]. The in vitro activity of micafungin Aspergillus versicolor (n = 3). However, minimum was determined against 5346 invasive (blood- effective concentrations were not reported [11–13]. stream or sterile site) isolates of Candida spp. In an experimental model of guinea pigs suf- collected from over 90 medical centers world- fering from invasive pulmonary aspergillosis, wide. Micafungin demonstrated high activity micafungin was markedly less effective than against Candida spp. with minimal inhibitory voriconazole or amphotericin B [14]. In another concentrations (MIC) of 0.015 µg/ml for 50% model, micafungin failed to eliminate invasive (MIC50) and 1 µg/ml for 90% (MIC90) of all pulmonary aspergillosis caused by a clinical iso- tested isolates (Table 1). Micafungin at doses of late of A. fumigatus in 27 neutropenic rabbits [15]. 2 µg/ml or less successfully inhibited all iso- However, in the treatment of an experimental lates. The least micafungin-susceptible strains, murine CNS aspergillosis, micafungin was more with MIC90 ranging from 1 to 2 µg/ml, were efficacious than voriconazole, caspofungin and Candida parapsilosis, Candida guilliermondii and conventional liposomal amphotericin B [16]. Candida famata. In an in vitro time-to-kill study, The in vitro activity of micafungin on micafungin did not exhibit fungicidal activity di morphic fungi considerably depends on their against C. parapsilosis [6]. In vivo, however, the growth form. Micafungin demonstrated good treatment response rate of micafungin against activity against mycelial forms of Histoplasma cap­ C. parapsilosis was comparable to those against sulatum, Blastomyces dermatitidis and Coccidioides immitis (MIC range 0.0078–0.0625 µg/ ml), as well as some activity against mycelial OH forms of Sporothrix schenckii (MIC ≤1 µg/ml) HO H O O and Penicillium marneffei (MIC ≤2 µg/ml). H SO Na OH H H H 3 However, against the yeast-like forms of these H N N 2 NH OH fungi and both forms of Paracoccidioides brasil­ H H iensis, the activity of micafungin was weak (MIC H N O O O OH range from 4 to >64 µg/ml) [17]. The reported H3C H O O N H MIC of micafungin against zygomycetes was H HO H greater than 8 µg/ml [11,13]. Micafungin does H NH CH3 HN not posses in vitro activity against important HO H OH basidio mycetes, such as Cryptococcus spp., O Rhodotorula spp. and Trichosporon spp. [12,13]. H OH H NH O H C 3 O N O Pharmacodynamics, pharmacokinetics & metabolism Micafungin is like all echinocandins, only avail- able for intravenous administration. It exhibits a Figure 1. Micafungin sodium. linear relationship between dose and area under Reproduced with permission from [102]. the plasma concentration–time curve (AUC) 556 Therapy (2010) 7(5) future science group Drug Evaluation Farowski, Vehreschild, Cornely & Vehreschild Micafungin in a nutshell: pharmacological & clinical aspects Drug Evaluation over the therapeutic dosing range of 50–150 mg Table 1. In vitro susceptibilities of 5346 clinical isolates of daily [18]. According to the package insert, no Candida spp. to micafungin. clinically
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