Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Antimycotics for systemic use, other antimycotics for systemic use, ATC code: J02AX05

Mode of action
Micafungin non-competitively inhibits the synthesis of 1,3-β-D-glucan, an essential component of the fungal cell wall. 1,3-β-D-glucan is not present in mammalian cells.
Micafungin exhibits fungicidal activity against most Candida species and prominently inhibits actively growing hyphae of Aspergillus species.

PK/PD relationship
In animals models of candidiasis, a correlation was observed between exposure of micafungin divided by MIC (AUC/MIC) and efficacy defined as the ratio required to prevent progressive fungal growth. A ratio of ~2400 and ~1300 was required for C. albicans and C. glabrata, respectively, in these models.
At the recommended therapeutic dosage of Mycamine, these ratios are achievable for the wild-type distribution of Candida spp.

Mechanism(s) of resistance
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 and Fks2 genes coding for a major subunit of glucan synthase.

Breakpoints
EUCAST breakpoints (version 10.0, valid from 2020-02-04)
Candida species                                 MIC breakpoint (mg/L) ≤S (Susceptible)               >R (Resistant)
Candida albicans                                0.016                          0.016 Candida glabrata                                0.03                           0.03 Candida parapsilosis                            2                              2 1
Candida tropicalis                              Insufficient evidence 1
Candida krusei                                  Insufficient evidence 1
Candida guilliermondii                          Insufficient evidence Other Candida spp.                              Insufficient evidence 1
MICs for C. tropicalis are 1-2 two-fold dilution steps higher than for C. albicans and C. glabrata. In the clinical study, successful outcome was numerically slightly lower for C. tropicalis than for C.
albicans at both dosages (100 and 150 mg daily). However, the difference was not significant and whether it translates into a relevant clinical difference is unknown. MICs for C. krusei are approximately 3 two-fold dilution steps higher than those for C. albicans and, similarly, those for C.
guilliermondii are approximately 8 two-fold dilutions higher. In addition, only a small number of cases involved these species in the clinical trials. This means there is insufficient evidence to indicate whether the wild-type population of these pathogens can be considered susceptible to micafungin.

Information from clinical studies
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; 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). 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.


Overall Treatment Success in the Per Protocol Set, Invasive Candidiasis Study Micafungin           Liposomal             % Difference
Amphotericin B             [95% CI]
N       n (%)        N       n (%)
Adult Patients
Overall Treatment Success         202     181 (89.6)   190     170 (89.5)   0.1 [-5.9, 6.1] † Overall Treatment Success by Neutropenic Status
Neutropenia at baseline       24      18 (75.0)    15      12 (80.0)    0.7 [-5.3, 6.7] ‡ No neutropenia at baseline    178     163 (91.6)   175     158 (90.3) Paediatric Patients
Overall Treatment Success         48      35 (72.9)    50      38 (76.0)    -2.7 [-17.3, 11.9] § < 2 years old                     26      21 (80.8)     31       24 (77.4) Premature Infants              10      7 (70.0)      9        6 (66.7) Neonates (0 days to            7       7 (100)       5        4 (80)
< 4 weeks)
2 to 15 years old                 22      14 (63.6)     19       14 (73.7)
Adults and Children Combined, Overall Treatment Success by Candida Species Candida albicans                       102     91 (89.2)     98       89 (90.8) Non-albicans species ¶: all            151     133 (88.1)    140      123 (87.9) C. tropicalis                     59      54 (91.5)     51       49 (96.1) C. parapsilosis                   48      41 (85.4)     44       35 (79.5) C. glabrata                       23      19 (82.6)     17       14 (82.4) C. krusei                         9       8 (88.9)      7        6 (85.7) † Micafungin rate minus the liposomal amphotericin B rate, and 2-sided 95% confidence interval for the difference in overall success rate based on large sample normal approximation.
‡ Adjusted for neutropenic status; primary endpoint.
§ The paediatric population was not sized to test for non-inferiority.
¶ Clinical efficacy was also observed (< 5 patients) in the following Candida species: C. guilliermondii, C.
famata, C. lusitaniae, C. utilis, C. inconspicua and C. dubliniensis.

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). 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 nature and incidence of adverse events were similar between treatment groups.

Prophylaxis: 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). 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).
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.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

Absorption
Pharmacokinetics are linear over the daily dose range of 12.5 mg to 200 mg and 3 mg/kg to 8 mg/kg.
There is no evidence of systemic accumulation with repeated administration and steady-state is generally reached within 4 to 5 days.

Distribution
Following intravenous administration concentrations of micafungin show a biexponential decline. The drug is rapidly distributed into tissues.
In systemic circulation, micafungin is highly bound to plasma protein (> 99%), primarily to albumin.
Binding to albumin is independent of micafungin concentration (10-100 µg/ml).
The volume of distribution at steady state (Vss) was approximately 18-19 litres.

Biotransformation
Unchanged micafungin is the principal circulating compound in systemic circulation. Micafungin has been shown to be metabolised to several compounds; of these M-1 (catechol form), M-2 (methoxy form of M-1) and M-5 (hydroxylation at the side chain) of micafungin have been detected in systemic circulation. Exposure to these metabolites is low and metabolites do not contribute to the overall efficacy of micafungin.
Even though micafungin is a substrate for CYP3A in vitro, hydroxylation by CYP3A is not a major pathway for micafungin metabolism in vivo.

Elimination and excretion
The mean terminal half-life is approximately 10-17 hours and stays consistent across doses up to 8 mg/kg and after single and repeated administration. Total clearance was 0.15-0.3 ml/min/kg in healthy subjects and adult patients and is independent of dose after single and repeated administration.
Following a single intravenous dose of 14C-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. These data indicate that elimination of micafungin is primarily non-renal. In plasma, metabolites M-1 and M-2 were detected only at trace concentrations and metabolite M-5, the more abundant metabolite, accounted for a total of 6.5% relative to parent compound.

Special populations
Paediatric patients: In paediatric patients AUC values were dose proportional over the dose range of 0.5-4 mg/kg. Clearance was 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 paediatric patients 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 children 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.

PK/PD bridging study demonstrated dose-dependent penetration of micafungin into CNS with the minimum AUC of 170 µg*hr/L required to achieve maximum eradication of fungal burden in the CNS tissues. Population PK modeling demonstrated that a dose of 10 mg/kg in children less than 4 month of age would be sufficient to achieve the target exposure for the treatment of CNS Candida infections.

Elderly: When administered as a single 1-hour infusion of 50 mg the pharmacokinetics of micafungin in the elderly (aged 66-78 years) were similar to those in young (20-24 years) subjects. No dose adjustment is necessary for the elderly.

Patients with hepatic impairment: In a study performed in patients with moderate hepatic impairment (Child-Pugh score 7-9), (n=8), the pharmacokinetics of micafungin did not significantly differ from those in healthy subjects (n=8). Therefore, no dose adjustment is necessary for patients with mild to moderate hepatic impairment. In a study performed in patients with severe hepatic impairment (Child- Pugh score 10-12) (n=8), lower plasma concentrations of micafungin and higher plasma concentrations of the hydroxide metabolite (M-5) were seen compared to healthy subjects (n=8). These data are insufficient to support a dosing recommendation in patients with severe hepatic impairment.

Patients with renal impairment: Severe renal impairment (Glomerular Filtration Rate [GFR] < 30 ml/min) did not significantly affect the pharmacokinetics of micafungin. No dose adjustment is necessary for patients with renal impairment.

Gender/Race: Gender and race (Caucasian, Black and Oriental) did not significantly influence the pharmacokinetic parameters of micafungin. No dose adjustment of micafungin is required based on gender or race.