60° Pharmaceuticals LLC, 1025 Connecticut Ave NW Suite 1000, Washington DC 20036, United States.
Clinical Network Services Pty Ltd, Level 4, 88 Jephson Road, Toowong, Queensland 4066, Australia.
Travel Med Infect Dis. 2017 May-Jun;17:28-34. doi: 10.1016/j.tmaid.2017.05.006. Epub 2017 May 8.
Tafenoquine is a new drug for malaria prevention. The goal of the present work was to conduct a specific neurobehavioral study in rats with histopathological assessment of the brain.
The clinical, hematological, behavioral, motor activity, and neurohistopathologic changes induced by different dose levels of tafenoquine were evaluated following single super-therapeutic dose administration. Toxicokinetic data were generated to allow extrapolation to clinical exposures.
At the highest dose (500 mg/kg), two animals (of 12) died. Surviving animals showed clinical signs of toxicity and had reduced body weight 7-8 days after dosing. Decreases in motor activity were observed on more than one occasion at doses > 9-fold higher than the clinical exposure. No statistically significant changes were observed for other behavioral endpoints. No neurohistopathological changes were noted. Changes in hematological and clinical pathology endpoints were observed at the lowest dose level (125 mg/kg). For context, the human dosing regimen is a 10 mg/kg load followed by 3.3 mg/kg weekly (in a 60 kg person).
As in humans, adverse events other than neurotoxicity were dose-limiting for tafenoquine in rats. This raises the prospect that a new weekly prophylactic, without neurologic liability, may become available in the near future.
替法诺喹是一种新的疟疾预防药物。本研究的目的是在大鼠中进行特定的神经行为研究，并对大脑进行组织病理学评估。
在单次超治疗剂量给药后，评估不同剂量水平的替法诺喹引起的临床、血液学、行为、运动活动和神经组织病理学变化。毒代动力学数据的生成允许外推至临床暴露。
在最高剂量（500mg/kg）下，有两只动物（共 12 只）死亡。存活的动物在给药后 7-8 天出现毒性临床症状和体重减轻。在高于临床暴露 9 倍以上的剂量下，多次观察到运动活动减少。其他行为终点没有观察到统计学上的显著变化。未观察到神经组织病理学变化。在最低剂量水平（125mg/kg）观察到血液学和临床病理学终点的变化。背景信息，人类的给药方案是 10mg/kg 负荷剂量，然后每周 3.3mg/kg（在 60kg 个体中）。
与人类一样，替法诺喹在大鼠中除神经毒性以外的不良事件是剂量限制因素。这使得一种新的、无神经毒性的每周预防性药物可能在不久的将来问世。
