Hyatt Michael W, Wiederhold Nathan P, Hope William W, Stott Katharine E
J Zoo Wildl Med. 2017 Jun;48(2):352-362. doi: 10.1638/2016-0160R2.1.
Aspergillosis is a common respiratory fungal disease in African penguins ( Spheniscus demersus ) under managed care, and treatment failures with itraconazole due to drug resistance are increasingly common, leading to recent use of voriconazole. Empirical dosing with voriconazole based on other avian studies has resulted in adverse clinical drug effects in penguins. The objective of this study was to determine oral voriconazole pharmacokinetics (PK) in African penguins (n = 18). Single and once daily multiple oral doses of 5 mg/kg voriconazole were evaluated with a 4-mo washout period between trials. Plasma voriconazole concentrations were determined via high-performance liquid chromatography. Data was modeled using 3-compartamental population methodologies that supported first-order elimination. Observed mean peak concentration (1.89 μg/ml) after single dosing PK analysis was determined within the first hour following voriconazole administration. In the multiple-dose trial average plasma voriconazole concentrations were significantly higher on days 4 and 7 as compared with day 2. The mean estimates for volume of distribution (V/F) and clearance (Cl/F) for the multiple-dose study were 3.34 L and 0.18 L/hr, respectively. Monte Carlo simulations determined the median area under the curve (AUC) at 84 hr was 37.7 μg·h/ml. As this assessment was comparable with the average AUC in humans receiving the recommended human oral dosage 200 mg b.i.d., it suggests that 5 mg/kg p.o. s.i.d. could be a safe and effective regimen in African penguins for treatment of aspergillosis. However, due to potential drug accumulation and subsequent toxicity, therapeutic drug monitoring with dosage adjustments is recommended to individualize dosing.
曲霉病是圈养管理下的非洲企鹅（斑嘴环企鹅）常见的呼吸道真菌病，因耐药导致伊曲康唑治疗失败的情况日益普遍，这促使近期开始使用伏立康唑。基于其他鸟类研究进行的伏立康唑经验性给药已在企鹅身上产生不良临床药物效应。本研究的目的是确定非洲企鹅（n = 18）口服伏立康唑的药代动力学（PK）。在试验之间设置4个月的洗脱期，对5 mg/kg伏立康唑的单次口服剂量和每日一次的多次口服剂量进行了评估。通过高效液相色谱法测定血浆伏立康唑浓度。使用支持一级消除的三室群体方法对数据进行建模。单次给药PK分析后观察到的平均峰值浓度（1.89 μg/ml）在伏立康唑给药后的第一小时内确定。在多剂量试验中，第4天和第7天的平均血浆伏立康唑浓度与第2天相比显著更高。多剂量研究的分布容积（V/F）和清除率（Cl/F）的平均估计值分别为3.34 L和0.18 L/hr。蒙特卡罗模拟确定84小时曲线下面积（AUC）的中位数为37.7 μg·h/ml。由于该评估与接受推荐的人类口服剂量200 mg bid的人类的平均AUC相当，这表明5 mg/kg口服每日一次可能是治疗非洲企鹅曲霉病的安全有效方案。然而，由于存在潜在的药物蓄积及随后的毒性，建议进行治疗药物监测并调整剂量以实现个体化给药。
