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

1582 13 days. Posaconazole is approved for prophylaxis against candidiasis
and aspergillosis in patients >13 years of age who have prolonged
neutropenia or severe graft-vs-host disease (GVHD)
(Ullmann et al., 2007). Posaconazole and other “azoles” have
recently been compared for prophylaxis effect in patients with neutropenia
(Cornely et al., 2007b). The broad applicability of posaconazole
for prophylaxis of patients with prolonged neutropenia or
GVHD remains unsettled, although the drug clearly remains an
option for those indications (De Pauw, 2007).
Posaconazole is approved in the E.U. as salvage therapy for
aspergillosis and several other infections, as are itraconazole and
voriconazole. A number of clinical reports of favorable response to
posaconazole as salvage therapy in mucormycosis have appeared in
the literature, leaving the issue unresolved (Dannaoui et al., 2003;
Greenberg et al., 2006). Lack of an intravenous formulation continues
to limit studies of critically ill patients.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Drug Interactions. Posaconazole inhibits CYP3A4. Co-administration
with rifabutin or phenytoin increases the plasma concentration
of these drugs and decreases posaconazole exposure by 2-fold. The
mechanism of induced posaconazole clearance is unknown but may
involve hepatic phase 2 glucuronidation, rather than phase 1 oxidative
enzymes. Oxidative products have not been recovered in the
serum of treated patients. Posaconazole increases the AUC of
cyclosporine, tacrolimus (121%), sirolimus (790%), midazolam
(83%) and other CYP3A4 substrates (Table 57–4) (Frampton and
Scott, 2008; Krishna et al., 2009a; Moton et al., 2009). Posaconazole
is not known to prolong cardiac repolarization, as other azoles may,
but posaconazole should not be co-administered with drugs that are
CYP3A4 substrates and prolong the QTc interval, such as
methadone, haloperidol, pimozide, quinidine, risperidone, sunitinib,
tacrolimus, and halofantrine (Table 57–6).
Untoward Effects. The safety profile of posaconazole is good, with
nausea, vomiting, diarrhea, abdominal pain, and headache the most
commonly reported adverse effects (Smith et al., 2009). Although
adverse effects occur in at least a third of patients, discontinuation
due to adverse effects in long-term studies has been only 8%,
Posaconazole causes fetal bone malformation in pregnant rats and is
pregnancy Category C. Safety in children <8 years of age has not
been established.
Dosage. Dosage for adults and children >8 years of age is 200 mg
(5 mL suspension) three times daily for prophylaxis. Treatment of
active infection is begun at 200 mg four times daily and changed to
400 mg twice daily once infection has improved. All doses should be
taken with a full meal.
Isavuconazole
Isavuconazole (BAL8557) is an investigational watersoluble
pro-drug of the synthetic triazole, BAL4815.
The pro-drug is readily cleaved by esterases in the human
body to release the active triazole. In vitro activity is comparable to
voriconazole (Guinea et al., 2008; Perkhofer et al., 2009).
Absorption, Distribution, and Excretion. Oral administration of
once-daily doses equivalent to 100 mg BAL4815 for loading followed
by 50 mg daily and 200 mg loading followed by 100 mg resulted in
peak plasma concentrations at 21 days of 1.37 μg/mL and 3.5 μg/mL
at 2.25 and 3.5 hours, respectively. The AUCs 0-24h
were 21.6 and 40.3
μg•h/mL, respectively (Schmitt-Hoffman et al., 2006). With intravenous
administration there was close to a linear dose response, with
a 5-fold accumulation over 14 days, a t 1/2
of 84.5-117 hours, and a
volume of distribution at steady state of 308-542 L. Excretion is by
the liver with most drug appearing in feces.
Therapeutic Use. Isavuconazole has been found comparable to
fluconazole in Candida esophagitis with all three isavuconazole
regimens tested: loading dose of 200 followed by 50 mg daily, loading
dose of 400 mg followed by 100 mg daily, or 400 mg once
weekly for 14 days (Odds, 2006). The drug was well tolerated.
Phase III trials are enrolling patients with deeply invasive candidiasis
and aspergillosis.
Echinocandins
Screening natural products of fungal fermentation in
the 1970s led to the discovery that echinocandins had
activity against Candida and that the biological activity
was directed against formation of 1,3-β-D-glucans in
the fungal cell wall (Wiederhold and Lewis, 2003). The
inhibition of glucan synthesis reduces structural
integrity of the fungal cell wall (Figure 57–3), resulting
in osmotic instability and cell death. Three
echinocandins are approved for clinical use: caspofungin,
anidulafungin, and micafungin. All are cyclic
lipopeptides with a hexapeptide nucleus. All have the
same mechanism of action but differ in pharmacological
properties. Susceptible fungi include Candida species
and Aspergillus species (Bennett, 2006).
General Pharmacological Characteristics. Echinocandins differ
somewhat pharmacokinetically (Table 57–7) but all share lack of oral
bioavailability, extensive protein binding (>97%), inability to penetrate
into CSF, lack of renal clearance, and only a slight to modest
effect of hepatic insufficiency on plasma drug concentration (Kim et
al., 2007; Wagner et al., 2006). Adverse effects are minimal and rarely
lead to drug discontinuation (Kim et al., 2007). All three agents are
pregnancy Category C. For a review of the basic and clinical pharmacology
of the echinocandins, see Wiederhold and Lewis (2007).
The minimum inhibitory concentration (MIC) of Candida
albicans and several other Candida species are in the range of
0.015-0.5 μg/mL, higher for caspofungin than micafungin or anidulafungin.
In Candida spp., echinocandins cause cell death at concentrations
only 2- to 4-fold higher than that needed to inhibit
growth. Azole-resistant Candida species remain susceptible to
echinocandins. MIC of Candida parapsilosis and C. guilliermondii
are consistently higher than other Candida spp., usually 2 μg/mL
with all three echinocandins. In none of the clinical trials of the three
echinocandins has the higher MIC of C. parapsilosis been reflected
in lower response rates. An unexplained and paradoxical effect of
increased growth at concentrations above the MIC has been seen
more often in C. parapsilosis than with other Candida spp. and more
commonly with caspofungin than micafungin or anidulafungin
(Chamilos et al., 2007). In Aspergillus, echinocandins are not cidal
but change the shape of hyphae; thus, in vitro susceptibility testing
is done with a “morphological” end point (change in hyphal shape).
Animal models do not suggest activity against dimorphic fungi such