Caspofungin

Method of Administration

After reconstitution and dilution, the solution should be administered by slow intravenous infusion over approximately 1 hour.  Both 70 mg and 50 mg vials are available.   Caspofungin should be given as a single daily infusion.

Uses

Caspofungin is an antifungal drug, and belongs to a new class termed the echinocandins. It is used to treat Aspergillus and Candida infection, and works by inhibiting cell wall synthesis. Antifungals in the echinocandin class inhibit the synthesis of glucan in the cell wall, probably via the enzyme 1,3-beta glucan synthase. There is a potential for resistance development to occur, however in vitro resistance development to Caspofungin by Aspergillus species has not been studied.

Definition

ChEBI: A semisynthetic cyclic hexapeptide echinocandin antibiotic which exerts its effect by inhibiting the synthesis of 1,3-beta-D-glucan, an integral component of the fungal cell wall.

Antimicrobial activity

It is active against Aspergillus spp., Candida spp. and the cyst form of Pn. jirovecii.

Acquired resistance

This is rare, but resistant strains of C. albicans, C. glabrata and C. parapsilosis have been recovered from patients failing caspofungin treatment. These strains are typically cross-resistant to other echinocandins.

Pharmaceutical Applications

A semisynthetic lipopeptide derived from a fermentation product of Glarea lozoyensis. Formulated as the diacetate for intravenous infusion.

Mechanism of action

Caspofungin inhibits the synthesis of beta-(1,3)-D-glucan, an essential component of the cell wall of Aspergillus species and Candida species. beta-(1,3)-D-glucan is not present in mammalian cells. The primary target is beta-(1,3)-glucan synthase.

Pharmacokinetics

C_max 70 mg 1-h infusion: c. 10 mg/L 1 h post infusion
Plasma half-life: 9–11 h
Volume of distribution: 0.15 L/kg
Plasma protein binding: 97%
Blood concentrations increase in proportion to dosage.
Distribution
The drug is widely distributed, the highest concentrations being found in the liver. Levels in the CSF are negligible.
Metabolism and excretion
It is slowly metabolized by the liver through non-enzymatic peptide hydrolysis and N-acetylation, and the two inactive metabolites are excreted in the feces and bile. No dosage adjustment is required in patients with renal impairment; however, a dose reduction to 35 mg following the 70 mg loading dose is recommended for patients with moderate hepatic impairment. Caspofungin is not cleared by hemodialysis.

Clinical Use

Candidemia and certain invasive forms of candidosis
Esophageal candidosis
Invasive aspergillosis unresponsive to other antifungal drugs
Empirical treatment of presumed fungal infections in febrile neutropenic patients

Side effects

Occasional histamine-mediated infusion-related reactions, injection site reactions and transient abnormalities of liver enzymes have been reported. Rare cases of significant hepatic dysfunction, hepatitis or worsening liver failure have also been described.

Drug interactions

Potentially hazardous interactions with other drugs
Ciclosporin: monitor liver enzymes as transient increases in ALT and AST have been reported with concomitant administration. Avoid coadministration if possible. Increases AUC of caspofungin by 35%.
Tacrolimus: reduces tacrolimus trough concentration by 26%.

Metabolism

Plasma concentrations of caspofungin decline in a polyphasic manner after intravenous infusion. The initial short α-phase occurs immediately post-infusion and is followed by a β-phase with a half-life of 9-11 hours; an additional longer γ-phase also occurs with a half-life of 40-50 hours. Plasma clearance is dependent on distribution rather than on biotransformation or excretion. Caspofungin undergoes spontaneous degradation to an open ring compound. There is further slow metabolism of caspofungin by hydrolysis and N-acetylation and excretion in faeces and urine