BACKGROUND & AIMS Pradefovir is a liver targeted novel prodrug of adefovir (PMEA) developed to provide higher antiviral activity with reduced systemic toxicities. This study evaluated the tolerability, pharmacokinetics, and antiviral activity of pradefovir in patients with chronic hepatitis B (CHB) virus infection. METHODS Non-cirrhotic, treatment-naïve subjects with CHB were divided into five groups (10 patients each) and randomized within each group in a ratio of 6:2:2 to receive an ascending dose of 30, 60, 75, 90, or 120 mg pradefovir, 10 mg adefovir dipivoxil (ADV), or 300 mg tenofovir disoproxil fumarate (TDF) once a day for 28 days. RESULTS A total of 51 subjects were randomized and 49 subjects completed the study. The groups were well matched and included 39 males, of whom 71% were hepatitis B e-antigen-negative with a mean hepatitis B virus (HBV) DNA level of 6.4-7.16 log10 IU/mL. No subject experienced a serious adverse event or nephrotoxicity. The most frequently reported adverse event was asymptomatic reduction in blood cholinesterase levels in the pradefovir group which recovered without any treatment about 13 ± 7 days after drug discontinuation. This adverse event was not observed in the ADV and TDF groups. The mean changes in serum HBV DNA were -2.78, -2.77, -3.08, -3.18, -3.44, -2.34, and -3.07 log10 IU/mL at 30, 60, 75, 90, and 120 mg pradefovir, 10 mg ADV and 300 mg TDF, respectively, with plateau levels reached with 60 mg pradefovir. Pradefovir and its metabolite PMEA showed linear pharmacokinetics proportional to the dose. The half-life of PMEA in the pradefovir group was 11.47-17.63 h. CONCLUSIONS Short-term use of pradefovir was well tolerated. A decline in HBV DNA levels was superior to TDF at higher doses of pradefovir. 30-60 mg pradefovir is recommended for CHB treatment. CLINICAL TRIAL NUMBER CTR20150224.

中文翻译：

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普来福韦治疗慢性乙型肝炎感染的安全性，有效性和药代动力学。

背景与目的普拉地福韦是一种针对肝脏的新型阿德福韦前药（PMEA），旨在提供更高的抗病毒活性和降低的系统毒性。这项研究评估了普拉德福韦在慢性乙型肝炎（CHB）病毒感染患者中的耐受性，药代动力学和抗病毒活性。方法将非肝硬化，未接受过治疗的CHB受试者分为5组（每组10位患者），并按6：2：2的比例在各组中随机分配，以接受30、60、75、90或90的递增剂量每天一次，一次120毫克pradefovir，10毫克阿德福韦酯（ADV）或300毫克替诺福韦二吡呋酯富马酸酯（TDF），持续28天。结果共有51名受试者被随机分组​​，其中49名受试者完成了研究。两组之间的匹配度很高，其中包括39名男性，其中71％的乙型肝炎e抗原阴性，平均乙型肝炎病毒（HBV）DNA水平为6.4-7.16 log10 IU / mL。没有受试者经历严重的不良事件或肾毒性。最常报告的不良事件是普拉德福韦组的血液胆碱酯酶水平无症状降低，在停药后约13±7天，未经任何治疗即可恢复。在ADV和TDF组中未观察到这种不良事件。在30、60、75、90和120 mg普地福韦，10 mg ADV时，血清HBV DNA的平均变化为-2.78，-2.77，-3.08，-3.18，-3.44，-2.34和-3.07 log10 IU / mL和300 mg TDF，分别达到60 mg普德福韦的平稳水平。普拉德福韦及其代谢物PMEA显示与剂量成比例的线性药代动力学。普拉德福韦组PMEA的半衰期为11.47-17.63 h。结论短期使用pradefovir的耐​​受性良好。在高剂量的普非佛韦中，HBV DNA水平的下降优于TDF。建议使用30-60 mg的普德福韦进行CHB治疗。临床试验号CTR20150224。