Micafungin (Mycamine)
Micafungin (Mycamine)
By Jessica C. Song, MA, PharmD, Kim Chu, PharmD Candidate, and Paul Hsiao, PharmD
Jessica C. Song is Assistant Professor of Pharmacy Practice, University of the Pacific, Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center, Section Editor, Managed Care, is Associate Editor for Infectious Disease Alert.
Kim Chu is PharmD Candidate, University of the Pacific, and Paul Hsiao is Clinical Pharmacist Specialist, Santa Clara Valley Medical Center
Jessica C. Song, Kim Chu, and Paul Hsiao report no consultant, stockholder, speaker’s bureau, research, or other financial relationship with companies having ties to this field of study.
Medical advances in recent decades have resulted in an increased frequency of invasive fungal infections. Specific patient-groups, such as the immunocompromised patients, are especially susceptible to fungal pathogens.1 Fifteen percent of allogeneic hematopoietic stem cell transplant (HSCT) patients experience invasive fungal infections, and about 10-15% of patients with AIDS are reported to develop esophageal candidiasis, occurring with or without oropharyngeal involvement.2 HSCT is associated with a high risk of invasive fungal infection caused by Candida and Aspergillus species.3 According to the current Infectious Disease Society of America (IDSA) guidelines for prophylaxis against opportunistic infections for HSCT patients, fluconazole represents the first-line agent for prevention of invasive disease induced by fluconazole-susceptible Candida species during neutropenic episodes. However, fluconazole is not effective against certain non-albicans species, including C. krusei and C. glabrata and is, therefore, not recommended for the prevention of infections caused by these molds.4 At present, fluconazole, itraconazole, voriconazole, and caspofungin are the preferred agents in the treatment of esophageal candidiasis observed in AIDS patients.5 However, resistance to fluconazole has been increasingly noted, and voriconazole6/itraconazole7/caspofungin8 interact with numerous drugs. In addition, there is evidence of enhanced hepatotoxicity with concomitant administration of caspofungin with cyclosporine.9
Micafungin is a semi-synthetic water-soluble lipopeptide antifungal agent of the echinocandin class.10 Echinocandins inhibit -1,3-D-glucan synthesis, thereby disrupting fungal cell wall structure, damaging cells, and inducing cell injury or death.1 Cell injury or death due to echinocandins may occur in regions of hyphal growth, particularly at branch points and advancing tips. However, other cells of the hyphal structure maintain their viability and may be recovered from tissue. In contrast, the effect of micafungin on Candida species is unique in that complete eradication of the organism from the tissue occurs during treatment.11 Micafungin sodium for injection was approved by the FDA on March 16, 2005, for the prophylaxis of Candida infections in patients undergoing HSCT, and for the treatment of esophageal candidiasis.12 This article will: 1) review the pharmacology, pharmacokinetics, and FDA indications of micafungin, 2) review its drug interactions, dosage, and resistance patterns, and 3) review the safety and efficacy of micafungin.
Spectrum of Activity
To date, susceptibility breakpoints for echinocandin agents have not been established. Moreover, since standardized methods to test the susceptibility patterns of this class of drugs have yet to be developed, MIC values should be interpreted with caution.1 Micafungin exhibits in vitro activity against a range of Candida species, including C. albicans (MIC90's 0.015-0.5 g/mL), C. dubliniensis (MIC90's 0.0156-0.5 g/mL), C. glabrata (MIC90's 0.0078-0.5 g/mL), C. guilliermondii (MIC90's 0.0313-2 g/mL), C. krusei (MIC90's 0.06-2 g/mL), C. parapsilosis (MIC90's 0.25-8 g/mL), and C. tropicalis (MIC90's 0.03-4 g/mL), in which it is fungicidal.13,14 Killing of these organism is very rapid, and a concentration-dependent postantifungal effect (PAFE) against Candida species of up to 10 hours has been reported.14 Micafungin has demonstrated potent in vitro activity against Aspergillus species, including A. fumigatus, A. flavus, A. niger, and A. terreus, with MIC90's ranging from 0.0078 to 0.25 g/mL.14 Interestingly, the PAFE of micafungin against A. fumigatus (0.5 hour) was shown to be considerably shorter than that observed against Candida species.14
Pharmacologic/Other Clinical Properties of Micafungin
Table 3 summarizes the mechanism of action, spectrum of activity, FDA indications, pharmacokinetics, dosing/administration, contraindications, adverse effects, drug interactions, resistance patterns, and cost of micafungin.
Clinical Efficacy of Micafungin
A review of literature showed that many of the clinical studies were comparative in nature, with fluconazole representing the most commonly observed drug of comparison for studies concerning prophylaxis of invasive fungal infections in neutropenic patients and treatment of esophageal candidiasis. Van Burik and colleagues conducted a randomized, double-blind, phase III trial (n = 882 adult/pediatric, neutropenic HSCT patients), in which once-daily 50 mg IV micafungin (1 mg/kg for patients weighing < 50 kg) was compared with once-daily 400 mg IV fluconazole (8 mg/kg for patients weighing < 50 kg) for the prophylaxis of invasive fungal infection. The primary end point was treatment success, which was defined as the absence of proven, probable, or suspected systemic fungal infection through the end of prophylaxis therapy, along with the absence of a proven or probable systemic fungal infection through the end of the 28-day post-treatment period.
Micafungin was shown to have a superior overall treatment success rate (absolute difference, +6.5%, 95% CI, 0.9 to 12%, P = 0.03), and was also more effective in reducing the need for empirical therapy (15.1% vs 21.4%, P = 0.024). Adverse events (resulting in discontinued use of study drug) trended in favor of micafungin (4.2% vs 7.2%, P = 0.058), but the only case of breakthrough zygomycosis occurred in a patient treated with micafungin.3
To date, 2 pivotal, randomized, double-blind, parallel-group trials have compared the efficacy of micafungin to that of fluconazole for the treatment of esophageal candidiasis.2,16 In general, the primary efficacy measure used in these studies was the endoscopic cure rate, defined as a mucosal grade of 0 at the end of treatment. In addition, the relapse rate frequency at 2 to 4 weeks post-treatment was assessed for micafungin- and fluconazole-treated patients. In one study, 523 patients with esophageal candidiasis were randomized to receive 150 mg/day IV micafungin or 200 mg/day IV fluconazole for a minimum of 2 weeks, or 1 week after resolution of symptoms.16 The primary end point was achieved by 87.7% and 88% of the micafungin- and fluconazole-treated patients, respectively (absolute difference, -0.3%, 95% CI, -5.9 to 5.3). No significant difference in relapse rates through 4 weeks post-treatment was noted among the treatment groups (15.2% for micafungin, 11.3% for fluconazole, P = 0.257). Similar to the results reported in the De Wet study,16 no significant difference in endoscopic cure rates was noted for 245 micafungin- (50, 100, 150 mg IV daily) and fluconazole- (200 mg IV daily) treated esophageal candidiasis patients (89.9% for micafungin 150 mg vs 86.7% for fluconazole 200 mg IV, P = 0.606).2 However, while the fluconazole-treated patients did not experience relapse at 2-weeks post-treatment, a 7% relapse rate was reported for patients treated with miconazole (P-value not reported). The overall safety and tolerability data from the 2 studies showed no clinically significant difference between micafungin and fluconazole.
At present, phase II or in vitro studies have assessed the efficacy of micafungin in patients with invasive aspergillosis and candidemia.17,18 Recently, an open-label Phase II study enrolled 283 patients (age 9 weeks to 84 years) with invasive aspergillosis (IA).17 Preliminary results indicate that micafungin (initial dose: 75 mg IV daily or 1.5 mg/kg if 40 kg; dose escalation permitted), alone or in combination, was an effective agent for primary and salvage therapy of IA. Response rates (complete or partial) were 45% and 33%, respectively, for all patients receiving monotherapy and for patients receiving salvage therapy (96% of patients on combination therapy). A multicenter, open-label clinical study in Japan18 yielded encouraging results in the use of micafungin for the treatment of deep-seated mycosis. Of the 70 patients who were treated with micafungin 12.5-150 mg IV/day, 6 patients had candidemia. All 6 patients were successfully treated with micafungin. At least 2 in vitro studies have evaluated the use of a combination of micafungin and conventional or new antifungals against isolates of Trichosporon sp., Sporobolomyces sp., Rhodotorula sp., and Scedosporium sp.19, 20
Conclusion
The echinocandins are a new class of antifungals that show potent in vitro activity against Candida sp and Aspergillus sp. Currently, there are 2 agents in this class, caspofungin and micafungin, which are only available for intravenous use. Caspofungin is indicated for empirical therapy of presumed fungal infections in febrile, neutropenic patients, treatment of candidemia, Candida infections (intra-abdominal abscesses, peritonitis, and pleural space infection), treatment of esophageal candidiasis, and treatment of invasive Aspergillosis in patients who are intolerant of, or refractory to, other therapies.8 In contrast, micafungin has only 2 indications: treatment of esophageal candidiasis and prophylaxis of Candida infections in patients undergoing HSCT.13 However, when compared to caspofungin, voriconazole, and itraconazole, micafungin is characterized by having a superior drug interaction profile. While micafungin has been shown to be as effective as fluconazole in the treatment of esophageal candidiasis, its therapeutic utility for this infection will probably be limited by the lack of an oral formulation. For aspergillosis, micafungin has been primarily used in combination with other antifungals for refractory infections. Both caspofungin and mica-fungin will play an important role in the treatment of infections due to azole-resistant Candida species, as both drugs maintain fungicidal activity against such pathogens. Pricing and additional clinical experience will likely influence the ultimate place of this new antifungal among the other members of its class.
References
- Denning DW. Echinocandin Antifungal Drugs. Lancet. 2003;362:1142-1151.
- de Wet N, et al. A Randomized, Double-Blind, Parallel-Group, Dose-Response Study of Micafungin Compared With Fluconazole for the Treatment of Esophageal Candidiasis in HIV-Positive Patients. Clin Infect Dis. 2004;39:842-849.
- Van Burik JA, et al. Micafungin Versus Fluconazole for Prophylaxis Against Invasive Fungal Infections During Neutropenia in Patients Undergoing Hematopoietic Stem Cell Transplantation. Clin Infect Dis. 2004;39:1407-1416.
- CDC, et al. Guidelines for Preventing Opportunistic Infections Among Hematopoietic Stem Cell Transplant Recipients. MMWR Recomm Rep. 2000;49:1-125. Erratum in: MMWR Recomm Rep. 2004;53:396.
- Benson CA, et al. Treating Opportunistic Infections Among HIV-Exposed and Infected Children: Recommendations From CDC, The National Institutes of Health, and the Infectious Diseases Society of America. MMWR Recomm Rep. 2004;53:1-112. Erratum in: MMWR Morb Mortal Wkly Rep. 2005;54:311.
- Voriconazole (Vfend) Prescribing Information. New York, NY: Pfizer; 2005 March.
- Itraconazole (Sporanox) Prescribing Information. Raritan, NJ: Ortho Biotech; 2004 January.
- Caspofungin (Cancidas®) Prescribing Information. Whitehouse Station, NJ: Merck & Co.: Feb 2005.
- Song JC, Deresinski S. Hepatotoxicity of Antifungal Agents. Curr Opin Investig Drugs. 2005;6:170-177.
- Pettengell K, et al. Successful Treatment of Oesophageal Candidiasis By Micafungin: A Novel Systemic Antifungal Agent. Aliment Pharmacol Ther. 2004;20:475-481.
- Petraitis V, et al. Combination Therapy in Treatment of Experimental Pulmonary Aspergillosis: Synergistic Interaction Between an Antifungal Triazole and an Echinocandin. J Infect Dis. 2003;187:1834-1843.
- Mosby's Drug Consult. Antifungal Prophylaxis Wins FDA Approval. New Drug Approval Updates 2005 Mar.
- Micafungin (Mycamine) Prescribing Information. Deerfield, Il: Astellas Pharma US: April 2005.
- Carver PL. Micafungin. Ann Pharmacother. 2004;38:1707-1721.
- Hiemenz J, et al. Pharmacokinetic and Maximum Tolerated Dose Study of Micafungin in Combination with Fluconazole Versus Fluconazole Alone for Prophylaxis of Fungal Infections in Adult Patients Undergoing a Bone Marrow or Peripheral Stem Cell Transplant. Antimicrob Agents Chemother. 2005;49:1331-1336.
- de Wet NT, et al. A Randomized, Double Blind, Comparative Trial of Micafungin (FK463) Vs. Fluconazole for the Treatment of Oesophageal Candidiasis. Aliment Pharmacol Ther. 2005;21:899-907.
- Ullman AJ, et al. An Open Phase II Study of the Efficacy of Micafungin (FK463) Alone and in Combination for the Treatment of Invasive Aspergillosis (IA) in Adults and Children. Thirteenth ECCMID meeting (2003), Glasgow, Scotland, UK.
- Kohno S, et al. A Multicenter, Open-Label Clinical Study of Micafungin (FK463) in the Treatment of Deep-Seated Mycosis in Japan. Scand J Infect Dis. 2004;36:372-379.
- Serena C, et al. In Vitro Interaction of Micafungin with Conventional and New Antifungals Against Clinical Isolates of Trichosporon, Sporobolomyces and Rhodotorula. J Antimicrob Chemother. 2005;55:1020-1023.
- Yustes C, Guarro J. In Vitro Synergistic Interaction Between Amphotericin B and Micafungin Against Scedosporium spp. Antimicrob Agents Chemother. 2005;49:3498-3500.
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