CLINICAL PHARMACOLOGY
Mechanism of Action
Micafungin is a member of the echinocandin class of antifungal agents [see Clinical Pharmacology ]
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Pharmacokinetics
Adults
The pharmacokinetics of micafungin were determined in healthy subjects, hematopoietic stem cell transplant recipients, and patients with esophageal candidiasis up to a maximum daily dose of 8 mg/kg body weight.
The relationship of area under the concentration-time curve (AUC) to micafungin dose was linear over the daily dose range of 50 mg to 150 mg and 3 mg/kg to 8 mg/kg body weight.
Steady-state pharmacokinetic parameters in relevant patient populations after repeated daily administration are presented in Table 7.
Table 7. Pharmacokinetic Parameters of Micafungin in Adult Patients
Population
|
n
|
Dose (mg)
|
Pharmacokinetic Parameters
(Mean ± Standard Deviation)
|
Cmax
(mcg/mL)
|
AUC0-24
(mcg·h/mL)
|
t½
(h)
|
Cl
(mL/min/kg)
|
Patients with IC
[Day 1]
|
20
|
100
|
5.7±2.2
|
83±51
|
14.5±7.0
|
0.359±0.179
|
[Steady State]
|
20
|
100
|
10.1±4.4
|
97±29
|
13.4±2.0
|
0.298±0.115
|
HIV
- Positive
Patients with EC
[Day 1]
|
20
20
14
|
50
100
150
|
4.1±1.4
8.0±2.4
11.6±3.1
|
36±9
108±31
151±45
|
14.9±4.3
13.8±3.0
14.1±2.6
|
0.321±0.098
0.327±0.093
0.340±0.092
|
[Day 14 or 21]
|
20
20
14
|
50
100
150
|
5.1±1.0
10.1±2.6
16.4±6.5
|
54±13
115±25
167±40
|
15.6±2.8
16.9±4.4
15.2±2.2
|
0.300±0.063
0.301±0.086
0.297±0.081
|
HSCT
Recipients
[Day 7]
|
8
10
8
8
|
per kg
3
4
6
8
|
21.1±2.84
29.2±6.2
38.4±6.9
60.8±26.9
|
234±34
339±72
479±157
663±212
|
14.0±1.4
14.2±3.2
14.9±2.6
17.2±2.3
|
0.214±0.031
0.204±0.036
0.224±0.064
0.223±0.081
|
Pediatric Patients 4 months of age and older
Micafungin pharmacokinetics in 229 pediatric patients 4 months through 16 years of age were characterized using population pharmacokinetics. Micafungin exposure was dose proportional across the dose and age range studied.
Table 8. Summary (Mean +/- Standard Deviation) of Micafungin Pharmacokinetics in Pediatric Patients 4 Months of Age and older (Steady-State)
Body weight group
|
N
|
Dose
mg/kg
|
Cmax.ss
(mcg/mL)
|
AUC.ss
(mcg·h /mL)
|
t½
(h)
|
CL
(mL/min/kg)
|
30 kg or less
|
149
|
1.0
|
7.1 +/- 4.7
|
55 +/- 16
|
12.5 +/- 4.6
|
0.328 +/- 0.091
|
2.0
|
14.2 +/- 9.3
|
109 +/- 31
|
3.0
|
21.3 +/- 14.0
|
164 +/- 47
|
Greater than 30 kg
|
80
|
1.0
|
8.7 +/- 5.6
|
67 +/- 17
|
13.6 +/- 8.8
|
0.241 +/- 0.061
|
2.0
|
17.5 +/- 11.2
|
134 +/- 33
|
2.5
|
23.0 +/- 14.5
|
176 +/- 42
|
Special Populations
Adult Patients with Renal Impairment
Mycamine does not require dose adjustment in patients with renal impairment. A single 1-hour infusion of 100 mg Mycamine was administered to 9 adult subjects with severe renal impairment (creatinine clearance less than 30 mL/min) and to 9 age-, gender-, and weight-matched subjects with normal renal function (creatinine clearance greater than 80 mL/min). The maximum concentration (Cmax) and AUC were not significantly altered by severe renal impairment.
Since micafungin is highly protein bound, it is not dialyzable. Supplementary dosing should not be required following hemodialysis.
Adult Patients with Hepatic Impairment
-
•A single 1-hour infusion of 100 mg Mycamine was administered to 8 adult subjects with moderate hepatic impairment (Child-Pugh score 7-9) and 8 age-, gender-, and weight-matched subjects with normal hepatic function. The Cmax and AUC values of micafungin were lower by approximately 22% in subjects with moderate hepatic impairment compared to normal subjects. This difference in micafungin exposure does not require dose adjustment of Mycamine in patients with moderate hepatic impairment.
-
•A single 1-hour infusion of 100 mg Mycamine was administered to 8 adult subjects with severe hepatic impairment (Child-Pugh score 10-12) and 8 age-, gender-, ethnic- and weight-matched subjects with normal hepatic function. The mean Cmax and AUC values of micafungin were lower by approximately 30% in subjects with severe hepatic impairment compared to normal subjects. The mean Cmax and AUC values of M-5 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 Mycamine dose adjustment is necessary in patients with severe hepatic impairment.
Distribution
The mean ± standard deviation volume of distribution of micafungin at terminal phase was 0.39 ± 0.11 L/kg body weight when determined in adult patients with esophageal candidiasis at the dose range of 50 mg to 150 mg.
Micafungin is highly (greater than 99%) protein bound in vitro, independent of plasma concentrations over the range of 10 to 100 mcg/mL. The primary binding protein is albumin; however, micafungin, at therapeutically relevant concentrations, does not competitively displace bilirubin binding to albumin. Micafungin also binds to a lesser extent to α1-acid-glycoprotein.
Metabolism
Micafungin is metabolized to M-1 (catechol form) by arylsulfatase, with further metabolism to M-2 (methoxy form) by catechol-O-methyltransferase. M-5 is formed by hydroxylation at the side chain (ω-1 position) of micafungin catalyzed by cytochrome P450 (CYP) isozymes. Even though micafungin is a substrate for and a weak inhibitor of CYP3A in vitro, hydroxylation by CYP3A is not a major pathway for micafungin metabolism in vivo. Micafungin is neither a P-glycoprotein substrate nor inhibitor in vitro.
In four healthy volunteer studies, the ratio of metabolite to parent exposure (AUC) at a dose of 150 mg/day was 6% for M-1, 1% for M-2, and 6% for M-5. In patients with esophageal candidiasis, the ratio of metabolite to parent exposure (AUC) at a dose of 150 mg/day was 11% for M-1, 2% for M-2, and 12% for M-5.
Excretion
The excretion of radioactivity following a single intravenous dose of 14C-micafungin sodium for injection (25 mg) was evaluated in healthy volunteers. At 28 days after administration, mean urinary and fecal recovery of total radioactivity accounted for 82.5% (76.4% to 87.9%) of the administered dose. Fecal excretion is the major route of elimination (total radioactivity at 28 days was 71% of the administered dose).
Microbiology
Mechanism of Action
Micafungin inhibits the synthesis of 1, 3-beta-D-glucan, an essential component of fungal cell walls, which is not present in mammalian cells.
Drug Resistance
There have been reports of clinical failures in patients receiving Mycamine therapy due to the development of drug resistance. Some of these reports have identified specific mutations in the FKS protein component of the glucan synthase enzyme that are associated with higher MICs and breakthrough infection.
Activity In Vitro and In Clinical Infections
Micafungin has been shown to be active against most isolates of the following Candida species, both
in vitro and in clinical infections:
Candida albicans
Candida glabrata
Candida guilliermondii
Candida krusei
Candida parapsilosis
Candida tropicalis
Susceptibility Testing Methods
The interpretive standards for micafungin against Candida species are applicable only to tests performed using Clinical Laboratory and Standards Institute (CLSI) microbroth dilution reference method M27-A3 for minimum inhibitory concentration (MIC; based on partial inhibition endpoint) and CLSI disk diffusion reference method M44-A2; both MIC and zone diameter results are read at 24 hours.
When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of pathogens. These reports should aid the physician in selecting an antifungal drug product for treatment. The techniques for Broth Microdilution and Disk Diffusion are described below.
Broth Microdilution Technique
Quantitative methods are used to determine antifungal MICs. These MICs provide estimates of the susceptibility of Candida species to antifungal agents. MICs should be determined using a standardized CLSI procedure1,2. Standardized procedures are based on a microdilution method (broth) with standardized inoculum concentrations and standardized concentrations of micafungin powder. The MIC values should be interpreted according to the criteria provided in Table 9.
Disk Diffusion Technique
Qualitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of Candida species to antifungal agents. The CLSI procedure3 uses standardized inoculum concentrations and paper disks impregnated with 10 mcg of micafungin to test the susceptibility of Candida species to micafungin at 24 hours. Disk diffusion interpretive criteria are provided in Table 9.
Table 9. Susceptibility Interpretive Criteria for Micafungin
Pathogen
|
Broth Microdilution MIC (mcg/mL)
at 24 hours
|
Disk Diffusion at 24 hours
(Zone diameters in mm)
|
Susceptible
(S)
|
Intermediate (I)
|
Resistant
(R)
|
Susceptible
(S)
|
Intermediate (I)
|
Resistant
(R)
|
Candida albicans
|
≤ 0.25
|
0.5
|
≥ 1
|
≥ 22
|
20-21
|
≤ 19
|
Candida tropicalis
|
≤ 0.25
|
0.5
|
≥ 1
|
≥ 22
|
20-21
|
≤ 19
|
Candida krusei
|
≤ 0.25
|
0.5
|
≥ 1
|
≥ 22
|
20-21
|
≤ 19
|
Candida parapsilosis
|
≤ 2
|
4
|
≥ 8
|
≥ 16
|
14-15
|
≤ 13
|
Candida guilliermondii
|
≤ 2
|
4
|
≥ 8
|
≥ 16
|
14-15
|
≤ 13
|
Candida glabrata
|
≤ 0.06
|
0.12
|
≥ 0.25
|
Not Applicable
|
Not Applicable
|
Not Applicable
|
MIC: minimum inhibitory concentration
|
A report of “Susceptible” indicates that the isolate is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable.
The “Intermediate” category implies that an infection due to the isolate may be appropriately treated in body sites where the drug is physiologically concentrated or when a high dosage of drug is used. The “Resistant” category implies that the isolates are not inhibited by the concentrations of the drug usually achievable with normal dosage schedules and clinical efficacy of the drug against the pathogen has not been reliably shown in treatment studies.
Quality Control
Standardized susceptibility test procedures require the use of quality control organisms to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the technique of the individual performing the test1, 2, 3. Standard micafungin powder and 10 mcg disks should provide the following range of values noted in Table 10.
Table 10. Acceptable Quality Control Ranges for Micafungin to be Used in Validation of Susceptibility Test Results
QC strains
|
Broth microdilution (MIC in mcg/mL) at 24- hour
|
Disk Diffusion
(Zone diameter in mm) at 24-hour
|
Candida parapsilosis ATCC
22019
|
0.5 – 2.0
|
14 – 23
|
Candida krusei ATCC 6258
|
0.12 – 0.5
|
23 – 29
|
Candida tropicalis ATCC 750
|
Not Applicable
|
24 – 30
|
Candida albicans ATCC 90028
|
Not Applicable
|
24 – 31
|
MIC: minimum inhibitory concentration
|
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Hepatic carcinomas and adenomas were observed in a 6-month intravenous toxicology study with an 18-month recovery period of micafungin sodium in rats designed to assess the reversibility of hepatocellular lesions.
Rats administered micafungin sodium for 3 months at 32 mg/kg/day (corresponding to 8 times the highest recommended human dose [150 mg/day], based on AUC comparisons), exhibited colored patches/zones, multinucleated hepatocytes and altered hepatocellular foci after 1 or 3 month recovery periods, and adenomas were observed after a 21-month recovery period. Rats administered micafungin sodium at the same dose for 6 months exhibited adenomas after a 12-month recovery period; after an 18-month recovery period, an increased incidence of adenomas was observed, and additionally, carcinomas were detected. A lower dose of micafungin sodium (equivalent to 5 times the human AUC) in the 6-month rat study resulted in a lower incidence of adenomas and carcinomas following 18 months recovery. The duration of micafungin dosing in these rat studies (3 or 6 months) exceeds the usual duration of Mycamine dosing in patients, which is typically less than 1 month for treatment of esophageal candidiasis, but dosing may exceed 1 month for Candida prophylaxis.
Although the increase in carcinomas in the 6-month rat study did not reach statistical significance, the persistence of altered hepatocellular foci subsequent to Mycamine dosing, and the presence of adenomas and carcinomas in the recovery periods suggest a causal relationship between micafungin sodium, altered hepatocellular foci, and hepatic neoplasms. Whole-life carcinogenicity studies of Mycamine in animals have not been conducted, and it is not known whether the hepatic neoplasms observed in treated rats also occur in other species, or if there is a dose threshold for this effect.
Micafungin sodium was not mutagenic or clastogenic when evaluated in a standard battery of in vitro and in vivo tests (i.e., bacterial reversion - S. typhimurium, E. coli; chromosomal aberration; intravenous mouse micronucleus).
Male rats treated intravenously with micafungin sodium for 9 weeks showed vacuolation of the epididymal ductal epithelial cells at or above 10 mg/kg (about 0.6 times the recommended clinical dose for esophageal candidiasis, based on body surface area comparisons). Higher doses (about twice the recommended clinical dose, based on body surface area comparisons) resulted in higher epididymis weights and reduced numbers of sperm cells. In a 39-week intravenous study in dogs, seminiferous tubular atrophy and decreased sperm in the epididymis were observed at 10 and 32 mg/kg, doses equal to about 2 and 7 times the recommended clinical dose, based on body surface area comparisons. There was no impairment of fertility in animal studies with micafungin sodium.
Animal Toxicology and/or Pharmacology
High doses of micafungin sodium (5 to 8 times the highest recommended human dose, based on AUC comparisons) have been associated with irreversible changes to the liver when administered for 3 or 6 months, and these changes may be indicative of pre-malignant processes [see Nonclinical Toxicology].
Reproductive Toxicology Studies
Micafungin sodium administration to pregnant rabbits (intravenous dosing on days 6 to 18 of gestation) resulted in visceral abnormalities and abortion at 32 mg/kg, a dose equivalent to about four times the recommended dose based on body surface area comparisons. Visceral abnormalities included abnormal lobation of the lung, levocardia, retrocaval ureter, anomalous right subclavian artery, and dilatation of the ureter.
|