Pharmacokinetics of isavuconazonium sulfate and its active metabolite isavuconazole in healthy dogs.

Invasive fungal infections (IFIs) are growing in importance in veterinary and human medicine. IFIs such as aspergillosis, blastomycosis, coccidioidomycosis and histoplasmosis remain challenging to treat in dogs. Isavuconazole is a novel antifungal medication that, when compared to currently used azoles, has an expanded spectrum of antifungal activity Rudramurthy (2011), Pfaller (2013), Spec (2018), has more predictable pharmacokinetics in humans Desai (2016), Cojutti (2021) and may cause fewer side effects such as liver and renal toxicity Maertens (2016), DiPippo (2018). The pharmacokinetic profile and safety of isavuconazole in dogs has not yet been characterized. The purpose of this study was to evaluate the pharmacokinetics of isavuconazole in healthy dogs that received a single dose of the prodrug isavuconazonium sulfate. Using full crossover design, six healthy beagle dogs received isavuconazonium sulfate at a mean (+/- SD) dose of 20.6 (+/- 2.8) mg/kg orally and 21.8 (+/- 4.2) mg/kg intravenously. Plasma was collected for batched pharmacokinetic analysis of prodrug and metabolite, isavuconazole, by ultra-high-pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). The median (Q1-Q3) maximum isavuconazole peak plasma concentration was estimated at 3,876.5 (2,811.0-4,800.0) ng/mL following oral administration, with a median (Q1-Q3) peak level at 1.3 (1.0-2.0) hours. Following intravenous administration, the median (Q1-Q3) isavuconazole peak plasma concentration was estimated at 3,221.5 (2,241.5-3,609.0) ng/mL, with a median (Q1-Q3) peak level at 0.4 (0.3-0.6) hours. The median (Q1-Q3) half-life of isavuconazole was 9.4 (7.0-12.2) hours and 14.0 (8.1-21.7) hours for oral and intravenous routes, respectively. One dog received inadvertent subcutaneous drug administration without any apparent adverse effects. Another dog experienced an anaphylactic reaction following accidental rapid drug infusion. No other drug-related adverse events were observed. At dosages used in this study, healthy dogs achieved isavuconazole plasma levels comparable to human therapeutic targets, and when properly administered the drug was well-tolerated.

Posaconazole followed by combination itraconazole and terbinafine for treatment of disseminated histoplasmosis in a cat.

OBJECTIVE: This is the first reported use of posaconazole for the treatment of feline disseminated histoplasmosis. ANIMALS: Approximately 1-year-old female spayed domestic longhair cat. CLINICAL PRESENTATION, PROGRESSION, AND PROCEDURES: The cat presented to our institution with weight loss, lymphadenomegaly, hepatosplenomegaly, limb edema, abdominal fluid distension and ulcerated cutaneous nodules. The cat had been previously diagnosed with disseminated histoplasmosis at another institution approximately 6 months prior. Clinical signs had been refractory to treatment with fluconazole. Itraconazole had next been tried, and the cat's weight continued to decline, lesions failed to regress, and the cat formed abdominal fluid distension and marked pelvic limb edema. TREATMENT AND OUTCOME: The cat was prescribed posaconazole along with prednisolone. The cat's demeanor, body weight, and lesions all markedly improved. Histoplasma antigen was undetectable in urine samples while the cat was receiving posaconazole. However, posaconazole blood levels paired with markedly elevated ALT suggested potential toxicity and the drug was discontinued. Upon cessation of posaconazole, the cat's lesions returned with cytologic evidence of intralesional Histoplasma yeast. Itraconazole combine with terbinafine was prescribed. At last follow-up, the cat was clinically well, off all anti-fungal medication, and without detectable Histoplasma antigen in the urine. CLINICAL RELEVANCE: Posaconazole therapy showed promise in this case. Had a safe and therapeutic dose been arrived at, we suspect that posaconazole would have cleared or maintained clinical remission of this cat's disease. This is the first report using posaconazole and the first successful report using combination itraconazole and terbinafine for the treatment of feline disseminated histoplasmosis. Generic drugs were used throughout this case report; the drug manufacturers are unknown to the authors.