Drug Metabolism and Pharmacokinetics, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
Nonclinical Safety, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
PLoS Negl Trop Dis. 2019 Jan 16;13(1):e0007026. doi: 10.1371/journal.pntd.0007026. eCollection 2019 Jan.
Flubendazole, originally developed to treat infections with intestinal nematodes, has been shown to be efficacious in animal models of filarial infections. For treatment of filarial nematodes, systemic exposure is needed. For this purpose, an orally bioavailable amorphous solid dispersion (ASD) formulation of flubendazole was developed. As this formulation results in improved systemic absorption, the pharmacokinetic and toxicological profile of the flubendazole ASD formulation have been assessed to ensure human safety before clinical trials could be initiated.
METHODS & FINDINGS: Safety pharmacology, toxicity and genotoxicity studies have been conducted with the flubendazole ASD formulation. In animals, flubendazole has good oral bioavailability from an ASD formulation ranging from 15% in dogs, 27% in rats to more than 100% in jirds. In in vivo toxicity studies with the ASD formulation, high systemic exposure to flubendazole and its main metabolites was reached. Flubendazole, up to high peak plasma concentrations, does not induce Cmax related effects in CNS or cardiovascular system. In repeated dose toxicity studies in rats and dogs, flubendazole-induced changes were observed in haematological, lymphoid and gastrointestinal systems and in testes. In dogs, the liver was an additional target organ. Upon treatment cessation, at least partial recovery was observed for these changes in dogs. In rats, the No Observed Adverse Effect Level (NOAEL) was 5 mg (as base)/kg body weight/day (mg eq./kg/day) in males and 2.5 mg eq./kg/day in females. In dogs, the NOAEL was lower than 20 mg eq./kg/day. Regarding genotoxicity, flubendazole was negative in the Ames test, but positive in the in vivo micronucleus test.
Based on these results, in combination with previously described genotoxicity and reproductive toxicity data and the outcome of the preclinical efficacy studies, it was concluded that no flubendazole treatment regimen can be selected that would provide efficacy in humans at safe exposure.
氟苯达唑最初是为治疗肠道线虫感染而开发的，已被证明在丝虫感染的动物模型中有效。为了治疗丝虫线虫，需要全身暴露。为此，开发了一种氟苯达唑口服生物利用度的无定形固体分散体（ASD）制剂。由于这种制剂导致系统吸收改善，因此在启动临床试验之前，评估了氟苯达唑 ASD 制剂的药代动力学和毒理学特征，以确保人类安全。
对氟苯达唑 ASD 制剂进行了安全药理学、毒性和遗传毒性研究。在动物中，从狗的 ASD 制剂中氟苯达唑的口服生物利用度为 15%，从大鼠的 27%到沙鼠的 100%以上。在 ASD 制剂的体内毒性研究中，达到了氟苯达唑及其主要代谢物的高全身暴露。氟苯达唑，直至高峰值血浆浓度，不会在中枢神经系统或心血管系统中引起 Cmax 相关作用。在大鼠和狗的重复剂量毒性研究中，观察到血液学、淋巴系统和胃肠道系统以及睾丸的氟苯达唑诱导变化。在狗中，肝脏是另一个靶器官。停药后，这些变化在狗中至少部分恢复。在大鼠中，雄性的无观察不良效应水平（NOAEL）为 5mg（以碱计）/kg 体重/天（mg eq./kg/天），雌性为 2.5mg eq./kg/天。在狗中，NOAEL 低于 20mg eq./kg/天。关于遗传毒性，氟苯达唑在 Ames 试验中为阴性，但在体内微核试验中为阳性。
基于这些结果，结合先前描述的遗传毒性和生殖毒性数据以及临床前疗效研究的结果，得出的结论是，没有可以选择的氟苯达唑治疗方案可以在安全暴露的情况下为人类提供疗效。
