Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, Iowa, United States of America.
Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, Iowa, United States of America.
PLoS One. 2024 Jul 16;19(7):e0305766. doi: 10.1371/journal.pone.0305766. eCollection 2024.
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.
在兽医和人类医学中，侵袭性真菌感染（IFI）的重要性日益增加。犬曲霉病、芽生菌病、球孢子菌病和组织胞浆菌病等 IFI 仍然难以治疗。伊曲康唑是一种新型抗真菌药物，与目前使用的唑类药物相比，具有更广泛的抗真菌活性 Rudramurthy（2011）、Pfaller（2013）、Spec（2018），在人类中具有更可预测的药代动力学特性 Desai（2016）、Cojutti（2021），并且可能引起更少的副作用，如肝和肾毒性 Maertens（2016）、DiPippo（2018）。伊曲康唑在犬中的药代动力学特征和安全性尚未得到描述。本研究的目的是评估健康犬单次给予前药伊曲康唑硫酸酯后的药代动力学。使用完全交叉设计，六只健康比格犬以平均（+/- SD）剂量 20.6（+/- 2.8）mg/kg 口服和 21.8（+/- 4.2）mg/kg 静脉内给予伊曲康唑硫酸酯。通过超高效液相色谱串联质谱法（UHPLC-MS/MS）对前药和代谢物伊曲康唑进行批处理药代动力学分析，收集血浆。口服给药后，伊曲康唑的最大血浆峰浓度中位数（Q1-Q3）估计为 3876.5（2811.0-4800.0）ng/mL，峰水平中位数（Q1-Q3）为 1.3（1.0-2.0）小时。静脉内给药后，伊曲康唑的最大血浆浓度中位数（Q1-Q3）估计为 3221.5（2241.5-3609.0）ng/mL，峰水平中位数（Q1-Q3）为 0.4（0.3-0.6）小时。伊曲康唑的中位数（Q1-Q3）半衰期分别为口服和静脉途径的 9.4（7.0-12.2）小时和 14.0（8.1-21.7）小时。一只狗在无意中接受皮下药物给药后没有出现任何明显的不良反应。另一只狗在意外快速药物输注后发生过敏反应。未观察到其他与药物相关的不良事件。在本研究中使用的剂量下，健康犬达到了与人类治疗目标相当的伊曲康唑血浆水平，并且在适当给药时药物耐受性良好。
