Efficacy of subcutaneous doses and a new oral amorphous solid dispersion formulation of flubendazole on male jirds (Meriones unguiculatus) infected with the filarial nematode Brugia pahangi

River blindness and lymphatic filariasis are two filarial diseases that globally affect millions of people mostly in impoverished countries. Current mass drug administration programs rely on drugs that primarily target the microfilariae, which are released from adult female worms. The female worms can live for several years, releasing millions of microfilariae throughout the course of infection. Thus, to stop transmission of infection and shorten the time to elimination of these diseases, a safe and effective drug that kills the adult stage is needed. The benzimidazole anthelmintic flubendazole (FBZ) is 100% efficacious as a macrofilaricide in experimental filarial rodent models but it must be administered subcutaneously (SC) due to its low oral bioavailability. Studies were undertaken to assess the efficacy of a new oral amorphous solid dispersion (ASD) formulation of FBZ on Brugia pahangi infected jirds (Meriones unguiculatus) and compare it to a single or multiple doses of FBZ given subcutaneously. Results showed that worm burden was not significantly decreased in animals given oral doses of ASD FBZ (0.2–15 mg/kg). Regardless, doses as low as 1.5 mg/kg caused extensive ultrastructural damage to developing embryos and microfilariae (mf). SC injections of FBZ in suspension (10 mg/kg) given for 5 days however, eliminated all worms in all animals, and a single SC injection reduced worm burden by 63% compared to the control group. In summary, oral doses of ASD formulated FBZ did not significantly reduce total worm burden but longer treatments, extended takedown times or a second dosing regimen, may decrease female fecundity and the number of mf shed by female worms.

盘尾丝虫病与淋巴丝虫病均为丝虫传染病，在全球范围内影响数百万人群，且主要流行于贫困国家。当前的大规模药物治疗项目主要依赖靶向雌性成虫丝虫所释放的微丝蚴的药物。雌性成虫丝虫可存活数年，在整个感染周期内持续释放数百万条微丝蚴。因此，为阻断感染传播并缩短疾病根除所需时长，亟需一款能够杀灭成虫阶段的安全有效药物。苯并咪唑类抗蠕虫药氟苯达唑（flubendazole, FBZ）在实验性丝虫感染的啮齿动物模型中作为丝虫成虫杀灭剂，可达到100%的杀虫效力，但由于其口服生物利用度极低，需经皮下注射（subcutaneously, SC）途径给药。本研究旨在评估一款新型口服氟苯达唑无定形固体分散体（amorphous solid dispersion, ASD）制剂，对感染彭亨布鲁丝虫（Brugia pahangi）的长爪沙鼠（Meriones unguiculatus）的杀虫效果，并将其与单次或多次皮下注射氟苯达唑的给药方案进行对比。实验结果显示，口服给药（剂量范围0.2~15 mg/kg）的ASD-FBZ组实验动物，其蠕虫负荷未出现显著降低。尽管如此，低至1.5 mg/kg的给药剂量即可对发育中的胚胎与微丝蚴（microfilariae, mf）造成广泛的超微结构损伤。然而，以悬浮液形式给予5天皮下注射FBZ（10 mg/kg）的方案，可完全清除所有实验动物体内的丝虫；单次皮下注射组则较对照组的蠕虫负荷降低63%。综上，口服ASD制剂氟苯达唑并未显著降低实验动物的总蠕虫负荷，但延长给药周期、延长取材观察时长或采用二次给药方案，或可降低雌性成虫丝虫的繁殖能力及其释放的微丝蚴数量。