Laboratory of Veterinary Internal Medicine, College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea.
Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea.
In Vivo. 2023 Sep-Oct;37(5):2128-2133. doi: 10.21873/invivo.13309.
BACKGROUND/AIM: Fingolimod is a sphingosine-1-phosphate receptor modulator that prevents lymphocytes egress from lymphoid organs. It has been used as a disease-modifying drug for human multiple sclerosis and has shown better therapeutic effects than other conventional therapies. Therefore, this study was performed to obtain preclinical data of fingolimod in dogs.
Nine laboratory Beagle dogs were used and randomized into three groups for pharmacokinetics (PK) and pharmacodynamics (PD). The dogs were administered once with a low-dose (0.01 mg/kg, n=3), medium-dose (0.05 mg/kg, n=3), and high-dose (0.1 mg/kg, n=3) of fingolimod, orally. Samples were collected serially at predetermined time points, and whole blood fingolimod concentrations were measured using high-performance liquid chromatography-mass spectrometry. Differential counts of leukocytes over time were determined to identify immune cells' response to fingolimod.
Regarding PK, the concentration of fingolimod in the blood increased in a dose-dependent manner, but it was not proportional. Regarding PD, the number of lymphocytes significantly decreased compared to baseline in all dose groups (low-dose, p=0.0002; medium-dose, p<0.0001; high-dose, p=0.0012). Eosinophils were significantly reduced in low- (p=0.0006) and medium- (p=0.0006) doses, and neutrophils were also significantly reduced in medium-(p=0.0345) and high- (p=0.0016) doses.
This study provides the basis for future clinical applications of fingolimod in dogs with immune-mediated diseases, such as meningoencephalitis of unknown etiology.
背景/目的：芬戈莫德是一种鞘氨醇-1-磷酸受体调节剂，可阻止淋巴细胞从淋巴器官迁出。它已被用作人类多发性硬化症的疾病修饰药物，并且显示出比其他常规疗法更好的治疗效果。因此，进行这项研究是为了在狗中获得芬戈莫德的临床前数据。
使用 9 只实验室比格犬，随机分为三组进行药代动力学（PK）和药效学（PD）研究。狗口服一次给予低剂量（0.01mg/kg，n=3）、中剂量（0.05mg/kg，n=3）和高剂量（0.1mg/kg，n=3）的芬戈莫德。在预定的时间点连续采集样本，使用高效液相色谱-质谱法测定全血中芬戈莫德的浓度。确定白细胞的时间差异计数以确定免疫细胞对芬戈莫德的反应。
关于 PK，血液中芬戈莫德的浓度呈剂量依赖性增加，但不成比例。关于 PD，与基线相比，所有剂量组的淋巴细胞数量均显著减少（低剂量，p=0.0002；中剂量，p<0.0001；高剂量，p=0.0012）。低剂量（p=0.0006）和中剂量（p=0.0006）组的嗜酸性粒细胞显著减少，中剂量（p=0.0345）和高剂量（p=0.0016）组的中性粒细胞也显著减少。
本研究为今后在患有免疫介导性疾病（如病因不明的脑膜脑炎）的狗中应用芬戈莫德提供了基础。
