DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1584 Metabolism and Excretion. Catabolism is largely by hydrolysis and
N-acetylation, with excretion of the metabolites in the urine and
feces. Mild and moderate hepatic insufficiency increases the AUC by
55% and 76%, respectively.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Drug Interactions. Caspofungin increase tacrolimus levels by 16%,
which should be managed by standard monitoring. Cyclosporine
slightly increases caspofungin levels. Rifampin and other drugs activating
CYP3A4 can cause a slight reduction in caspofungin levels.
Therapeutic Use. Caspofungin is approved for initial therapy of
deeply invasive candidiasis and as salvage therapy for patients with
invasive aspergillosis who are failing or intolerant of approved drugs,
such as amphotericin B formulations or voriconazole. Approval for
salvage therapy of aspergillosis was based on a study of 63 patients
in a noncomparative salvage trial. Caspofungin is also approved for
esophageal candidiasis, based on randomized trials that found noninferiority
to fluconazole and C-AMB (Villanueva et al., 2001). A
blinded randomized clinical trial of caspofungin in deeply invasive
candidiasis found noninferiority to C-AMB, leading to approval for
that indication (Mora-Duarte et al., 2002). Most patients in that multicenter
study were not neutropenic and had catheter-acquired candidemia.
Efficacy was comparable to that of fluconazole in other
studies of the same general patient population. Caspofungin is also
approved for the treatment of persistently febrile neutropenic patients
with suspected fungal infections, based on noninferiority to L-AMB
in a randomized trial (Walsh et al., 2004b).
Untoward Effects. Caspofungin has been remarkably well tolerated,
with the exception of phlebitis at the infusion site. Histamine-like
effects have been reported with rapid infusions. Other symptoms
have been equivalent to those observed in patients receiving fluconazole
in the comparator arm.
Dosage. Caspofungin is administered intravenously once daily over
1 hour. In candidemia and salvage therapy of aspergillosis, the initial
dose is 70 mg, followed by 50 mg daily. The dose should be
increased to 70 mg daily in patients receiving rifampin as well as in
those failing to respond to 50 mg. Esophageal candidiasis is treated
with 50 mg daily. In moderate hepatic failure, the dose should be
reduced to 35 mg daily.
Micafungin
Micafungin (MYCAMINE) is a water-soluble semisynthetic
echinocandin derived from the fungus Coleophoma
empedri.
Absorption, Distribution, and Excretion. Micafungin has linear
pharmacokinetics over a large range of doses (1-3 mg/kg) and ages
(premature infants to elderly). Feces contain 71% of intravenously
administered radiolabeled drug, including both native drug and metabolites
(Wiederhold and Lewis, 2007). Small amounts of drug are metabolized
in the liver by arylsulfatase and catechol O-methyltransferase.
Hydroxylation by CYP3A4 is barely detectable. Reduction of dose in
moderate hepatic failure is not required. Clearance is more rapid in premature
infants and intermediate in children 2-8 years of age, compared
to older children and adults.
Drug Interactions. In normal volunteers, micafungin appears to be
a mild inhibitor of CYP3A4, increasing AUC of nifedipine by 18%
OH
O
O
S O
and sirolimus by 21%. Micafungin has no effect on tacrolimus
clearance.
Therapeutic Use. Micafungin is approved for the treatment of
deeply invasive candidiasis (Fritz et al., 2008). Doses of 100 mg and
150 mg daily of micafungin were equivalent to caspofungin (Pappas
et al., 2007). Micafungin, 100 mg/day, was also not inferior to
L-AMB, 3 mg/kg (Kuse et al., 2007). Micafungin is also approved
for treatment of esophageal candidiasis and prophylaxis of deeply
invasive candidiasis in hematopoietic stem cell transplant recipients.
Doses. Micafungin is given intravenously as 100 mg daily over 1 hour
for adults, with 50 mg recommended for prophylaxis and 150 mg for
esophageal candidiasis. No loading dose is needed.
Anidulafungin
Anidulafungin (ERAXIS) is a water-insoluble semisynthetic
compound extracted from the fungus Aspergillus
nidulans, from which the drug’s name derives.
HO
H 3 C
H 3 C
H 2 N
HO
HO
O
HO
H 3 C
O
HO
N
HO
O
NH
OH
HO
HO
O
HO
O
H
N
N
NH
O
O
O
NH
OH
MICAFUNGIN
HN
O
OH
N
HO
H
N
NH
O
O
O
HN
NH
O
OH
CH 3
OH
OH
N
ANIDULAFUNGIN
NH
O
O
OH
CH 3
OH
H 3 C
H 3 C
O
N
O
O