VORICONAZOLE
Voriconazole is a fluconazole derivative, but it has a higher intrinsic activity against many fungal organisms. Voriconazole
is available as 50- and 200-mg tablets. The typical cost of voriconazole for a 44-lb dog (5 mg/kg orally twice a day) is about
$40/day.
Potential indications
Voriconazole is the drug of choice for invasive Aspergillus species infections in people because of its fungicidal activity and its safety as compared with amphotericin B.16 Voriconazole also has activity against many organisms such as Aspergillus, Candida, Cryptococcus, and Fusarium species that develop resistance to other azoles.16
Pharmacokinetics
Voriconazole's plasma protein binding is intermediate (about 51%).31 Complete absorption occurs in dogs receiving oral voriconazole with a CMAX of 6.5 μg/ml at three hours after a single 6 mg/kg dose.20 Voriconazole penetrates the CNS and is effective against CNS fungal infections.16
Voriconazole primarily undergoes hepatic metabolism with the metabolites excreted in the urine and feces.31 About 5% of the total dose is eliminated in the urine of dogs as unchanged drug with an approximate 4.5-hour half-life after
a single dose.
The plasma concentration of voriconazole remained above the minimum fungicidal concentration against Aspergillus species for 24 hours after a single 6-mg/kg oral dose in dogs.31 However, multiple doses resulted in increased metabolism of voriconazole and subsequently reduced drug exposure as measured
by the area under the curve with 16 days of treatment. Increasing the dose of voriconazole from 3 mg/kg to 12 mg/kg, a fourfold
increase, resulted in a disproportionate increase in area under the curve—a ninefold increase. Therefore, dose adjustments
must be made cautiously.31
There are no reports of the pharmacokinetics of voriconazole in cats.
Adverse effects
The liver was the primary organ affected in toxicology studies, but the kidneys and adrenal glands may also be affected, and
anemia may occur.32 Evidence of hepatotoxicosis occurred in acute (30 days at 24 mg/kg) and chronic (six to 12 months at 12 mg/kg) toxicology
studies in dogs, including cell necrosis and increased alanine transaminase and alkaline phosphatase activities. Increased
liver weight, centrilobular hypertrophy, proliferation of smooth endoplasmic reticulum, and induction of CYP occurred in a
dose-dependent manner.32
Administration of intravenous voriconazole (10 mg/kg) in dogs resulted in unspecified acute toxicosis.32 In rats, high intravenous doses (50 mg/kg) resulted in CNS signs such as mydriasis, titubation (loss of balance during movement),
depression, prostration, extensor rigidity, ptosis, and dyspnea.32 In people, voriconazole produced unspecified changes in the retina at therapeutic drug concentrations, which resulted in
blurred vision; the visual effects were reversible, and no histopathologic changes were observed.32
Voriconazole can exhibit drug-drug interactions similar to fluconazole's. Additionally, concurrent administration of phenobarbital
may increase the metabolism of voriconazole with subsequent decreased efficacy.16
POSACONAZOLE
Posaconazole is an itraconazole derivative recently approved by the FDA for use in people and is available as a 40-mg/ml suspension.
The typical cost of posaconazole for a 44-lb dog (5 mg/kg orally once a day) is about $11/day.
Potential indications
Posaconazole has similar activity as the other azoles except that it has increased activity against resistant strains of Aspergillus and Candida species.33
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