化合物信息

Drug Groups

approved; investigational

Description

Micafungin is an antifungal drug. It belongs to the antifungal class of compounds known as echinocandins and exerts its effect by inhibiting the synthesis of 1,3-beta-D-glucan, an integral component of the fungal cell wall.

Indication

For use in the treatment of candidemia, acute disseminated candidiasis, and certain other invasive Candida infections, as well as esophageal candidiasis, and prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation. Micafungin is also used as an alternative for the treatment of oropharyngeal candidiases and has been used with some success as primary or salvage therapy, alone or in combination with other antifungals, for the treatment of invasive aspergillosis.

Pharmacology

Formerly known as FK463, micafungin is a semisynthetic lipopeptide synthesized from a fermentation product of Coleophoma empetri that works as an antifungal agent. It is a glucan synthesis inhibitor of the echinocandin structural class. The U.S. Food and Drug Administration approved micafungin in March 2005. Micafungin inhibits an enzyme essential for fungal cell-wall synthesis. Depending on its concentration, micafungin may be fungicidal against some Candida, but is usually fungistatic against Apergillus. Micafungin can be used concomitantly with a variety of other drugs, including the HIV protease inhibitor ritonavir and the transplant medications cyclosporine and tacrolimus.

Toxicity

Intravenous LD₅₀ in rats is 125mg/kg. In dogs it is >200mg/kg. No cases of overdosage have been reported. Repeated daily doses up to 8 mg/kg (maximum total dose of 896 mg) in adult patients have been administered in clinical trials with no reported dose-limiting toxicity. The minimum lethal dose is 125 mg/kg in rats, equivalent to 8.1 times the recommended human clinical dose for esophageal candidiasis based on body surface area comparisons.

Affected Organisms

Biotransformation

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 (w-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.

Absorption

Not absorbed orally

Half Life

14-17 hours

Protein Binding

Highly (>99%) protein bound in vitro, independent of plasma concentrations over the range of 10 to 100 µg/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 a₁-acid-glycoprotein.

Elimination

Fecal excretion is the major route of elimination (total radioactivity at 28 days was 71% of the administered dose).

Distribution

* 0.39 ± 0.11 L/kg [adult patients with esophageal candidiasis]

Clearance

* 0.359 +/- 0.179 mL/min/kg [Adult Patients with IC with 100 mg]
* 0.321 +/- 0.098 mL/min/kg [HIV- Positive Patients with EC with 50 mg]
* 0.327 +/- 0.093 mL/min/kg [HIV- Positive Patients with EC with 100 mg]
* 0.340 +/- 0.092 mL/min/kg [HIV- Positive Patients with EC with 150 mg]
* 0.214 +/- 0.031 mL/min/kg [hematopoietic stem cell transplant recipients 3 mg/kg]
* 0.204 +/- 0.036 mL/min/kg [hematopoietic stem cell transplant recipients 4 mg/kg]
* 0.224 +/- 0.064 mL/min/kg [hematopoietic stem cell transplant recipients 6 mg/kg]
* 0.223 +/- 0.081 mL/min/kg [hematopoietic stem cell transplant recipients 8 mg/kg]

References

External Links