Pharmacokinetics of isavuconazole in healthy cats after oral and intravenous administration

Abstract

Background: Isavuconazole is a triazole antifungal drug that has shown good efficacy in human patients. Absorption and pharmacokinetics have not been evaluated in cats.Objectives: To determine the pharmacokinetics of isavuconazole in cats given a single IV or PO dose.Animals: Eight healthy, adult research cats.Methods: Four cats received 100 mg capsules of isavuconazole PO. Four cats received 5 mg/kg isavuconazole solution IV. Serum was collected at predetermined intervals for analysis using ultra-high performance liquid chromatography-tandem mass spectrometry. Data were analyzed using a 2-compartment uniform weighting pharmacokinetic analysis with lag time for PO administration and a 2 compartment, 1/y 2 weighting for IV administration. Predicted 24 and 48-hour dosing intervals of 100 mg isavuconazole administered PO were modeled and in vitro plasma protein binding was assessed.Results: Both PO and IV drug administration resulted in high serum concentrations.Intravenous and PO formulations of isavuconazole appear to be able to be used interchangeably. Peak serum isavuconazole concentrations occurred 5 ± 3.8 hours after PO administration with an elimination rate half-life of 66.2 ± 55.3 hours. Intersubject variability was apparent in both the PO and IV groups. Two cats vomited 6 to 8 hours after PO administration. No adverse effects were observed in the IV group.Oral bioavailability was estimated to be approximately 88%. Serum protein binding was calculated to be approximately 99.0% ± 0.03%. Conclusions and Clinical Importance:Isavuconazole might prove to be useful in cats with fungal disease given its favorable pharmacokinetics. Additional studies on safety, efficacy, and tolerability of long-term isavuconazole use are needed.

Therapeutic efficacy of isavuconazole and potassium iodide in a cat with refractory sporotrichosis

“…4 Evaluation of isavuconazole pharmacokinetics in healthy cats demonstrated that both oral and intravenous of administration result in high serum concentrations and are generally well-tolerated. 11 In the case reported here, the addition of this antifungal agent resulted in clinical resolution of all lesions and clinical signs after three months of therapy, without adverse effects and no evidence of recurrence for a one-year follow-up period. To the best of the authors' knowledge, this is the first documented report of the clinical use of isavuconazole in veterinary medicine.…”

“…The most commonly reported adverse effects in people are nausea, vomiting and diarrhoea and to a lesser extent drug‐related hepatotoxicity 4 . Evaluation of isavuconazole pharmacokinetics in healthy cats demonstrated that both oral and intravenous routes of administration result in high serum concentrations and are generally well‐tolerated 11 . In the case reported here, the addition of this antifungal agent resulted in clinical resolution of all lesions and clinical signs after three months of therapy, without adverse effects and no evidence of recurrence for a one‐year follow‐up period.…”

Invasive fungal infections and oomycoses in cats 2. Antifungal therapy

“…< Adverse effects Vomiting was observed 6 and 8 h after dosing in two of four cats administered a single 100 mg ISA capsule. 23 In humans, AEs are infrequent and usually limited to mild nausea, vomiting and diarrhoea; also, hepatotoxicity and drug-drug inter actions are uncommon compared with other tri azole antifungals. 47 < Clinical use only single-dose IV and oral pharmacokinetic data (Tables 1 and 2) are available for cats.…”

“…47 < Clinical use only single-dose IV and oral pharmacokinetic data (Tables 1 and 2) are available for cats. 23 Reports of use of ISA in the field are not yet available. Based on in vitro data and human studies, ISA would not be indicated for empirical therapy of SoA in cats.…”