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
Cmax 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
