Micafungin clinical pharmacology

# Clinical Pharmacology

## Mechanism of Action
Micafungin is a member of the echinocandin class of antifungal agents.

## 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.
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.

## Special Populations
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.
-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 1-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 (-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).8 USE IN

## SPECIFIC POPULATIONS

### Pregnancy
Pregnancy Category C. There are no adequate and well-controlled studies of Mycamine in pregnant women. Animal reproduction studies in rabbits showed visceral abnormalities and increased abortion at 4 times the recommended human dose. However, animal studies are not always predictive of human response. Mycamine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
When pregnant rabbits were given 4 times the recommended human dose, there were increased abortion and visceral abnormalities including abnormal lobation of the lung, levocardia, retrocaval ureter, anomalous right subclavian artery, and dilatation of the ureter .

### Nursing Mothers
It is not known whether micafungin is excreted in human milk. Caution should be exercised when Mycamine is administered to a nursing woman.

### Pediatric Use
Safety and effectiveness in pediatric patients younger than 4 months of age have not been established.
Safety and effectiveness of Mycamine in pediatric patients 4 months of age and older have been demonstrated based on the evidence from adequate and well-controlled studies in adult and pediatric patients and additional pediatric pharmacokinetic and safety data.  Two randomized, double-blind, active control studies investigated the safety and efficacy of Mycamine in both adult and pediatric patients: one for the treatment of invasive candidiasis and candidemia and the other for prophylaxis of Candida infections in patients undergoing HSCT .

### Geriatric Use
A total of 418 subjects in clinical studies of Mycamine were 65 years of age and older, and 124 subjects were 75 years of age and older. No overall differences in safety and effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
The exposure and disposition of a 50 mg Mycamine dose administered as a single 1-hour infusion to 10 healthy subjects aged 66-78 years were not significantly different from those in 10 healthy subjects aged 20-24 years. No dose adjustment is necessary for the elderly.

### Use in Patients with Renal Impairment
Mycamine does not require dose adjustment in patients with renal impairment. Supplementary dosing should not be required following hemodialysis .

### Use in Patients with Hepatic Impairment
Dose adjustment of Mycamine is not required in patients with mild, moderate, or severe hepatic impairment .

### Race and Gender
No dose adjustment of Mycamine is required based on gender or race. After 14 daily doses of 150 mg to healthy subjects, micafungin AUC in women was greater by approximately 23% compared with men, due to smaller body weight. No notable differences among white, black, and Hispanic subjects were seen. The micafungin AUC was greater by 19% in Japanese subjects compared to blacks, due to smaller body weight.

### Drug Abuse And Dependence
There has been no evidence of either psychological or physical dependence or withdrawal or rebound effects with Mycamine.