Page 872 - Basic _ Clinical Pharmacology ( PDFDrive )

858 SECTION VIII Chemotherapeutic Drugs

TABLE 48–2 Pharmacologic properties of six systemic azole drugs.

CSF: Serum
Water Solubility Absorption Concentration Ratio t ½ (hours) Elimination Formulations
Ketoconazole Low Variable <0.1 7–10 Hepatic Oral
Itraconazole Low Variable <0.01 24–42 Hepatic Oral, IV
Fluconazole High High >0.7 22–31 Renal Oral, IV
Voriconazole High High >0.21 6 Hepatic Oral, IV
Posaconazole Low High — 25 Hepatic Oral, IV
Isavuconazole High High — 130 Hepatic Oral, IV

also useful in the treatment of intrinsically amphotericin-resistant the azole of choice for aspergillosis. Itraconazole is used extensively
organisms such as P boydii. in the treatment of dermatophytoses and onychomycosis.
As a group, the azoles are relatively nontoxic. The most com-
mon adverse reaction is relatively minor gastrointestinal upset. All
azoles have been reported to cause abnormalities in liver enzymes FLUCONAZOLE
and, very rarely, clinical hepatitis. Adverse effects specific to indi-
vidual agents are discussed below. Fluconazole displays a high degree of water solubility and good
All azole drugs are prone to drug interactions because cerebrospinal fluid penetration. Unlike ketoconazole and itracon-
they affect the mammalian cytochrome P450 enzyme system azole, its oral bioavailability is high. Drug interactions are also less
to some extent. The most significant reactions are indicated common because fluconazole has the least effect of all the azoles
below. on hepatic microsomal enzymes. Because of fewer hepatic enzyme
interactions and better gastrointestinal tolerance, fluconazole has
the widest therapeutic index of the azoles, permitting more aggres-
KETOCONAZOLE sive dosing in a variety of fungal infections. The drug is available
in oral and intravenous formulations and is used at a dosage of
Ketoconazole was the first oral azole introduced into clinical 100–800 mg/d.
use. It is distinguished from triazoles by its greater propensity to Fluconazole is the azole of choice in the treatment and
inhibit mammalian cytochrome P450 enzymes; that is, it is less secondary prophylaxis of cryptococcal meningitis. Intravenous
selective for fungal P450 than are the newer azoles. As a result, fluconazole has been shown to be equivalent to amphotericin B
systemic ketoconazole has fallen out of clinical use in the USA and in treatment of candidemia in ICU patients with normal white
is not discussed in any detail here. It is no longer recommended blood cell counts, although echinocandins may have superior
for the treatment of fungal nail or skin infections. activity for this indication. Fluconazole is the agent most com-
monly used for the treatment of mucocutaneous candidiasis.
ITRACONAZOLE Activity against the dimorphic fungi is mainly limited to coccidi-
oidal disease, and in particular for meningitis, where high doses
of fluconazole often obviate the need for intrathecal ampho-
Itraconazole is available in oral and intravenous formulations tericin B. Fluconazole displays no activity against Aspergillus or
and is used at a dosage of 100–400 mg/d. Drug absorption from other filamentous fungi.
capsules is increased by food and by low gastric pH. Like other Prophylactic use of fluconazole has been demonstrated to
lipid-soluble azoles, it interacts with hepatic microsomal enzymes, reduce fungal disease in bone marrow transplant recipients and
though to a lesser degree than ketoconazole. An important drug AIDS patients, but the emergence of fluconazole-resistant fungi
interaction is reduced bioavailability of itraconazole when taken has raised concerns about this indication.
with rifamycins (rifampin, rifabutin, rifapentine). It does not affect
mammalian steroid synthesis, and its effects on the metabolism of
other hepatically cleared medications are much less than those of VORICONAZOLE
ketoconazole. While itraconazole displays potent antifungal activ-
ity, effectiveness can be limited by reduced bioavailability. Newer Voriconazole is available in intravenous and oral formulations.
formulations, including an oral liquid and an intravenous prepara- The recommended dosage is 400 mg/d. The drug is well absorbed
tion, have utilized cyclodextrin as a carrier molecule to enhance orally, with a bioavailability exceeding 90%, and it exhibits less
solubility and bioavailability. Like ketoconazole, itraconazole protein binding than itraconazole. Metabolism is predominantly
penetrates poorly into the cerebrospinal fluid. Itraconazole is the hepatic. Voriconazole is a clinically relevant inhibitor of mam-
azole of choice for treatment of disease due to the dimorphic fungi malian CYP3A4, and dose reduction of a number of medica-
Histoplasma, Blastomyces, and Sporothrix. Itraconazole has activity tions is required when voriconazole is started. These include
against Aspergillus sp, but it has been replaced by voriconazole as cyclosporine, tacrolimus, and HMG-CoA reductase inhibitors.