Bridges Edward G, Selden Jules R, Luo Shouqi
Idenix Pharmaceuticals, Inc., One Kendall Square, Cambridge, Massachusetts 02139, USA.
Antimicrob Agents Chemother. 2008 Jul;52(7):2521-8. doi: 10.1128/AAC.00029-08. Epub 2008 May 12.
Telbivudine is a novel nucleoside drug recently approved for the treatment of patients with chronic hepatitis B. Its nonclinical safety was evaluated in a comprehensive program of studies, including safety pharmacology, acute and chronic toxicity, reproductive and developmental toxicity, genotoxicity, and carcinogenicity. There were no test article-related effects observed in an in vitro hERG assay or in a core battery of safety pharmacology studies (central nervous system, respiratory, and cardiovascular safety pharmacology studies). Telbivudine was well tolerated in rats and in monkeys following single oral doses up to 2,000 mg/kg/day. Except for equivocal axonopathic findings in monkeys and occasional incidences of emesis, soft feces, and minor changes in body weight and food consumption, there was no target organ toxicity observed in mice, rats, or monkeys following oral administration for up to 3, 6, or 9 months, respectively, at doses up to 3,000 mg/kg/day. Axonopathy in the sciatic nerves and in the spinal cords of monkeys dosed at 1,000 mg/kg/day observed in a 9-month study was considered equivocal, as the role of telbivudine in the injury could not be determined. Slightly higher incidences of abortion and premature delivery observed in rabbits dosed at 1,000 mg/kg/day were considered secondary to maternal toxicity. There was no evidence of genotoxicity or carcinogenicity. These results suggest that telbivudine has a favorable safety profile and support its use in patients with chronic compensated hepatitis B viral infection.
替比夫定是一种最近被批准用于治疗慢性乙型肝炎患者的新型核苷类药物。其非临床安全性在一系列综合研究中进行了评估，包括安全药理学、急性和慢性毒性、生殖和发育毒性、遗传毒性以及致癌性。在体外人乙醚 - 去极化激活的钾离子通道（hERG）试验或一组核心安全药理学研究（中枢神经系统、呼吸系统和心血管系统安全药理学研究）中未观察到与受试物相关的影响。单次口服剂量高达2000mg/kg/天，替比夫定在大鼠和猴子中耐受性良好。分别以高达3000mg/kg/天的剂量口服给药3、6或9个月后，在小鼠、大鼠或猴子中，除了猴子出现不明确的轴索性病变以及偶尔出现呕吐粪便变软、体重和食物摄入量的轻微变化外，未观察到靶器官毒性。在一项为期9个月的研究中，给予1000mg/kg/天剂量的猴子坐骨神经和脊髓出现轴索性病变被认为不明确，因为无法确定替比夫定在损伤中的作用。在给予1000mg/kg/天剂量的兔子中观察到的流产和早产发生率略高被认为是母体毒性的继发效应。没有遗传毒性或致癌性的证据。这些结果表明替比夫定具有良好的安全性，并支持其用于慢性代偿性乙型肝炎病毒感染患者。
