Micafungin, the active ingredient of MYCAMINE, is a member of the echinocandin lipopeptide family and inhibits non-competitively the synthesis of 1,3-β-D-glucan, an essential component of fungal cell walls which is not present in mammalian cells.
Candidaemia and Invasive Candidiasis: Micafungin (100 mg/day or 2 mg/kg/day) was as effective as and better tolerated than liposomal amphotericin B (3 mg/kg) as first-line treatment of candidaemia and invasive candidiasis in a randomised, double-blind, multinational non-inferiority study. Micafungin and liposomal amphotericin B were received for a median duration of 15 days (range 4 to 42 days in adults and 12 to 42 days in children).
Non-inferiority was proven for adult patients, and similar findings were demonstrated for the paediatric subpopulations (including neonates and premature infants). Efficacy findings were consistent, independent of the infective Candida
species, primary site of infection and neutropenic status (see Table 1). Micafungin demonstrated a smaller mean peak decrease in estimated glomerular filtration rate during treatment (p < 0.001) and a lower incidence of infusion-related reactions (p = 0.001) than liposomal amphotericin B.
MYCAMINE has not been adequately studied in patients with endocarditis, osteomyelitis and meningitis due to Candida infections. (See Table 1.)
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Oesophageal Candidiasis: In a randomised, double-blind study of micafungin versus fluconazole in the first-line treatment of oesophageal candidiasis, 518 patients received at least a single dose of study drug. The median treatment duration was 14 days and the median average daily dose was 150 mg for micafungin (N = 260) and 200 mg for fluconazole (N = 258). Most patients in this study had HIV infection. An endoscopic grade of 0 (endoscopic cure) at the end of treatment was observed for 87.7% (228/260) and 88.0% (227/258) of patients in the micafungin and fluconazole groups, respectively (95% CI for difference: [-5.9%, 5.3%]). The lower limit of the 95% CI was above the predefined non-inferiority margin of -10%, proving non-inferiority. The odds of endoscopic cure was approximately 2.6 times higher in HIV patients with a baseline CD4 count ≥100 than in HIV patients with a baseline CD4 count <100. All efficacy findings were consistent and showed micafungin to be as effective as fluconazole in adult oesophageal candidiasis patients, with similar rates of endoscopic cure, clinical resolution of the infection, mycological eradication, dynamics or improvement and incidence of relapse. The nature and incidence of adverse events were also similar between treatment groups.
Prophylaxis of Invasive Fungal Infection: Micafungin was more effective than fluconazole in preventing invasive fungal infections in a population of patients at high risk of developing a systemic fungal infection (patients undergoing haematopoietic stem cell transplantation [HSCT] in a randomised, double-blind, multicentre study). Treatment success was defined as the absence of a proven, probable, or suspected systemic fungal infection through the end of therapy and absence of a proven or probable systemic fungal infection through the end of study. Most patients (97%, N = 882) had neutropenia at baseline (< 200 neutrophils/μL) and neutropenia persisted for a median of 13 days. There was a fixed daily dose of 50 mg (1.0 mg/kg) for micafungin and 400 mg (8 mg/kg) for fluconazole. The mean period of treatment was 19 days for micafungin and 18 days for fluconazole in the adult population (N = 798) and 23 days for both treatment arms in the paediatric population (N = 84). Table 2 summarises the main efficacy findings. (See Table 2.)
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The rate of treatment success was statistically significantly higher for micafungin than fluconazole (1.6% versus 2.4% breakthrough infections). Breakthrough Aspergillus
infections were observed in 1 versus 7 patients, and proven or probable breakthrough Candida
infections were observed in 4 versus 2 patients in the micafungin and fluconazole groups, respectively. Other breakthrough infections were caused by Fusarium
(1 and 2 patients, respectively) and Zygomycetes
(1 and 0 patients, respectively). The nature and incidence of adverse reactions were similar between treatment groups.
The pharmacokinetics of micafungin have been evaluated in healthy subjects, haematopoietic stem cell transplant recipients and patients with invasive and oesophageal candidiasis up to a maximum dose of 8mg/kg. There is no evidence of systemic accumulation with repeated administration and increases in systemic exposure (AUC and Cmax
) are proportional to increases in dose. Steady-state is generally reached by Day 4.
Following intravenous administration, concentrations of micafungin show a bi-exponential decline as the drug is rapidly distributed into tissues. Micafungin is highly protein bound (>99%), primarily to albumin and to a lesser extent to alpha-1-acid glycoprotein. Binding to albumin is independent of micafungin concentration (10 to 100 μg/mL). Micafungin does not displace albumin-bound bilirubin at clinically relevant concentrations.
In an in vitro
study in which 14
C-micafungin was added to whole human blood, the blood to plasma ratio was approximately 0.85 and was independent of concentration over the range of 0.1 to 10 μg/mL micafungin.
The volume of distribution of micafungin at terminal phase was 0.24 to 0.41 L/kg body weight.
Unchanged micafungin is the principal circulating compound in the systemic circulation. Metabolism takes place in the liver where micafungin is metabolised to M1 (catechol form) by arylsulfatase, with further metabolism to M2 (methoxy form) by catechol-O- methyltransferase. M5 is formed by hydroxylation at the side chain (ω-1 position) of micafungin catalysed by cytochrome P450 (CYP) isoenzymes. Exposure to these metabolites is generally low and they are not expected to contribute to the overall efficacy of micafungin. Although micafungin is a substrate for CYP3A in vitro
, hydroxylation by CYP3A is not a major pathway for metabolism in vivo
The mean terminal half-life of micafungin is approximately 10 to 17 hours and stays consistent across doses up to 8mg/kg after single and repeated administration in patients and healthy volunteers. Faecal excretion is the major route of elimination. Following a single intravenous dose of 14
C-micafungin (25 mg) to healthy volunteers, 11.6% of the radioactivity was recovered in the urine and 71.0% in the faeces over 28 days.
Pharmacokinetic characteristics in special populations:
Patients with hepatic impairment: A single 1-hour infusion of 100 mg micafungin was administered to eight subjects with moderate hepatic impairment (Child-Pugh score 7 to 9) and eight age, gender and weight matched subjects with normal hepatic function. The pharmacokinetics of micafungin did not differ significantly from those in healthy subjects.
A single 1-hour infusion of 100mg micafungin was administered to eight subjects with severe hepatic impairment (Child-Pugh score 10 to 12) and eight age, gender, ethnic and weight matched subjects with normal hepatic function. The Cmax
and AUC values of micafungin were lower by approximately 30% in subjects with severe hepatic impairment compared to normal subjects. The Cmax
and AUC values of M5 metabolite were approximately 2.3-fold higher in subjects with severe hepatic impairment compared to normal subjects. However, this exposure (parent and metabolite) was comparable to that in patients with systemic Candida infection. Therefore, no micafungin dose adjustment is necessary in patients with mild to severe hepatic impairment.
Patients with renal impairment: A single 1-hour infusion of 100 mg micafungin was administered to nine subjects with severe renal impairment (creatinine clearance < 30 mL/min) and to nine subjects with normal renal function (creatinine clearance > 80 mL/min) who were age, gender and weight matched. The Cmax
and AUC were not significantly altered by severe renal impairment. No dose adjustment is necessary for patients with renal impairment.
Elderly: A single 1-hour infusion of 50 mg micafungin was administered to ten healthy subjects aged 66 to 78 years and ten healthy subjects aged 20 to 24 years. The pharmacokinetics of micafungin showed a similar time-course profile in both the elderly and young, and there were no significant differences in the pharmacokinetic parameters. No dose adjustment is necessary for the elderly.
Paediatric use: In paediatric patients, micafungin exposure is dose proportional in the dose range of 0.5-4 mg/kg, and up to 10 mg/kg in infants less than 4 months of age. Clearance is influenced by weight, with mean values of weight-adjusted clearance 1.35 times higher in the younger children (4 months to 5 years) and 1.14 times higher in children aged 6 to 11 years. Older children (12-16 years) had mean clearance values similar to those determined in adult patients. Mean weight-adjusted clearance in infants less than 4 months of age is approximately 2.6-fold greater than older children (12-16 years) and 2.3-fold greater than in adults. Weight-adjusted clearance differences support weight-based dosing up to body weights within the range of 40 (treatment) to 50 kg (prophylaxis), above which adult dosing is recommended.
Micafungin dosed at 4 mg/kg in infants less than 4 months approximates drug exposures achieved in adults receiving 100 mg/day for the treatment of invasive candidiasis. Higher doses (e.g., 10 mg/kg) may be required to treat CNS infection in infants less than 4 months of age as demonstrated by a PK-PD bridging study that showed dose-dependent penetration of micafungin into the CNS to achieve maximum eradication of fungal burden in the CNS tissues. Population PK modeling demonstrated that a dose of 10 mg/kg in infants less than 4 months of age would be sufficient to achieve the target exposure for the treatment of CNS Candida infections.
Gender and race: Gender or race (Caucasian, Black, Oriental) did not significantly influence the pharmacokinetic parameters of micafungin. No dose adjustment is required based on gender or race.
Micafungin exhibits fungicidal activity against most Candida
species and prominently inhibits actively growing hyphae of Aspergillus
activity: Susceptibility testing was performed with modifications according to the Clinical and Laboratory Standards Institute (CLSI) methods M27-A2 (Candida
species) and M38-A (Aspergillus
Micafungin displayed inhibitory activity against clinically relevant Candida
species. The Minimum Inhibitory Concentration (MIC) rank order was: C. albicans
(including azole resistant strains) C. tropicalis
, C. glabrata, C. krusei
, C. parapsilosis, C. gulliermondii.
Micafungin displayed inhibitory activity against clinically relevant Aspergillus
species (A. fumigatus
, A. niger, A. flavus
, A. nidulans
, A. terreus
and A. versicolor
Micafungin has virtually no activity against Cryptococcus neoformans
, Trichosporon cutaneum
, Trichosporon asahii
, Fusarium solani
, Pseudallescheria boydii
, Absidia corymbifera
, Cunninghamella elegans
, Rhizopus oryzae
or Rhizopus microsporus
activity: Micafungin was effective in the treatment of disseminated candidiasis, as well as against oropharyngeal and oesophageal candidiasis.
As for all antimicrobial agents, cases of reduced susceptibility and resistance have been reported and cross-resistance with other echinocandins cannot be excluded. Reduced susceptibility to echinocandins has been associated with mutations in the Fks1 gene coding for a major subunit of glucan synthase.