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

the maintenance dose. There are no data to guide dosing in patients
with severe hepatic insufficiency.
The intravenous formulation of voriconazole contains sulfobutyl
ether β-cyclodextrin (SBECD). When voriconazole is given
intravenously, SBECD is excreted completely by the kidney.
Significant accumulation of SBECD occurs with a creatinine clearance
<50 mL/minute. Because toxicity of SBECD at high plasma
concentrations is unclear, oral voriconazole is preferred in azotemic
patients.
Drug Interactions. Voriconazole is metabolized by, and inhibits,
CYPs 2C19, 2C9, and CYP3A4 (in that order of decreasing potency)
The major metabolite of voriconazole, the voriconazole N-oxide,
also inhibits these CYPs. Inhibitors or inducers of these CYPs may
increase or decrease voriconazole plasma concentrations, respectively.
In addition, there is potential for voriconazole and its major
metabolite to increase the plasma concentrations of other drugs
metabolized by these enzymes (Tables 57–3, 57–4, and 57–5).
Because the sirolimus AUC increases 11-fold when voriconazole is
given, co-administration is contraindicated. When starting voriconazole
in a patient receiving ≥40 mg/day of omeprazole, the dose of
omeprazole should be reduced by half.
Therapeutic Uses. In an open randomized trial, voriconazole provided
superior efficiency to C-AMB in the primary therapy of invasive
aspergillosis (Herbrecht et al., 2002). In a secondary analysis,
survival also was superior in the voriconazole arm. Voriconazole
was compared to L-AMB in an open randomized trial in the empirical
therapy of neutropenic patients whose fever did not respond to
>96 hours of antibacterial therapy. Because the 95% confidence
interval in this noninferiority trial permitted the possibility that
voriconazole might be >10% worse than L-AMB, the Food and
Drug Administration did not approve voriconazole for this use
(Walsh et al., 2002). However, in a secondary analysis, there were
fewer breakthrough infections with voriconazole (1.9%) than with
L-AMB (5%). Voriconazole is approved for use in esophageal candidiasis
on the basis of a double-blind randomized comparison with
fluconazole (Ally et al., 2001). In non-neutropenic patients with
candidemia, voriconazole was comparable in efficacy and less toxic
than initial C-AMB followed by fluconazole (Kullberg, 2005).
Voriconazole is approved for initial treatment of candidemia and
invasive aspergillosis, as well as for salvage therapy in patients with
Pseudallescheria boydii (Scedosporium apiospermum) and Fusarium
infections. Positive response of patients with cerebral fungal suggest
that the drug penetrates infected brain.
Untoward Effects. Voriconazole is teratogenic in animals and generally
contraindicated in pregnancy (Category D). Women of childbearing
potential should use effective contraception during
treatment. Although voriconazole is generally well tolerated, occasional
cases of hepatotoxicity have been reported, and liver function
should be monitored. Voriconazole, like some other azoles,
causes a prolongation of the QTc interval, which can become significant
in patients with other risk factors for torsades de pointes.
Patients must be warned about possible visual effects. Transient
visual or auditory hallucinations are frequent after the first dose,
usually at night and particularly with intravenous administration.
Symptoms diminish with time (Zonios et al., 2008). Patients
receiving their first intravenous infusion have had anaphylactoid
reactions, with faintness, nausea, flushing, feverishness, and rash.
In such patients, the infusion should be stopped. Rash has been
reported in 5.8% of patients.
Dosage. Voriconazole for intravenous infusion is packaged as 200
mg with 3.2 g SBECD. Treatment is usually initiated with an intravenous
infusion of 6 mg/kg every 12 hours for two doses, followed
by 3-4 mg/kg every 12 hours. It should be administered no faster
than 3 mg/kg/hr (e.g., over 1-2 hours, not as an intravenous bolus).
As the patient improves, oral administration is continued as 200 mg
every 12 hours. Patients failing to respond may be given 300 mg
every 12 hours. Voriconazole is available as 50- or 200-mg tablets or
a suspension of 40 mg/mL when hydrated. The tablets, but not the
suspension, contain lactose. Because high-fat meals reduce voriconazole
bioavailability, oral drug should be given either 1 hour before or
1 hour after meals. Children metabolize voriconazole more rapidly
that adults (Walsh, 2004a).
Posaconazole
Posaconazole (NOXAFIL) is a synthetic structural analog of itraconazole
with the same broad antifungal spectrum but with up to
4-fold greater activity in vitro against yeasts and filamentous
fungi, including the agents of mucormycosis (Guinea et al., 2008;
Frampton, 2008). Activity against yeasts in vitro is similar to
voriconazole. The mechanism of action is the same as other imidazoles,
inhibition of sterol 14-α demethylase.
Absorption, Distribution, and Excretion. Posaconazole is available
as a cherry-flavored suspension containing 40 mg/mL.
Bioavailability is significantly enhanced by the presence of food
(Courtney et al., 2003; Krieter, 2004). The drug has a long terminal
phase t 1/2
(25-31 hours), a large volume of distribution (331-1341 L),
and extensive binding (>98%) to protein, predominantly albumin.
Systemic exposure is four times higher in homozygous CYP2C19
slow metabolizers than in homozygous wild-type metabolizers.
Steady-state concentrations are reached in 7-10 days when dosed
four times daily. Saturation of absorption occurs at 800 mg/day
(Ezzet et al., 2005; Ullmann et al., 2006). Renal impairment does
not alter plasma concentrations; hepatic impairment causes a modest
increase (Moton, 2008). With radiolabeled drug given to volunteers,
77% was excreted in the stool, with 66% of the administered
dose appearing as unchanged drug. The major metabolic pathway is
hepatic UDP glucuronidation (Krieter, 2004). Hemodialysis does not
remove detectable amounts of this highly protein-bound drug from
the circulation. Gastric acid improves absorption in that an acidic
beverage, ginger ale, increased the AUC by 70% in the fasting state
(Krishna et al., 2009b). Drugs that reduce gastric acid (e.g., cimetidine
and esomeprazole) decreased posaconazole exposure by 32-
50% (Frampton and Scott, 2008). Diarrhea reduced the average
plasma concentration by 37% (Smith et al., 2009). Plasma concentrations
in allogeneic stem cell transplant recipients were 52% lower
than in patients not receiving a stem cell transplant (Ullmann et al.,
2006). Although monitoring plasma concentrations has been advocated
(Smith et al., 2009), the lower limit of therapeutic effect for any
indication is unknown.
Therapeutic Use. Posaconazole is not inferior to fluconazole for
treatment of oropharyngeal candidiasis, although fluconazole is the
preferred drug because of safety, cost, and extensive experience. The
dose is 100 mg twice daily the first day and once daily thereafter for
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CHAPTER 57
ANTIFUNGAL AGENTS