National Cancer Center Hospital, Tokyo National Cancer Center East Hospital, Kashiwa City, Chiba, Japan.
Hepatol Res. 2011 Jun;41(6):542-52. doi: 10.1111/j.1872-034X.2011.00800.x. Epub 2011 Apr 19.
NIK-333 (an acyclic retinoid) has been reported to prevent recurrence of hepatocellular carcinoma (HCC) in patients after curative treatment. This study was conducted to determine the maximum tolerated dose, dose-limiting toxicities (DLT) and pharmacokinetics of NIK-333 administrated p.o. at doses ranging 300-900 mg/day.
Patients who were cancer-free after percutaneous local ablation or surgical resection of HCC were enrolled. The total daily dose was administrated as a single dose (single-dose stage) followed by a week of rest, and then in two equally divided doses administrated after breakfast and supper for 48 consecutive weeks (repeated-dose stage).
No patients at the dose levels of 300 mg/day and 600 mg/day developed any DLT. At the final dose level of 900 mg/day, three of the nine patients developed grade 3 hypertension as a DLT. There were no significant difference values of maximum drug concentration (C(max) ) and log(C(max) ) between fasting and postprandial condition. In the repeated-dose stage, there was no significant difference between the start and week 24 of NIK-333 administration within any dose cohort in either the mean area under the blood concentration time curve (0-6 h) or the C(max) . NIK-333 was well-tolerated when administrated p.o. at doses of up to 600 mg/day for 48 weeks.
Hypertension was noted as a DLT at the dose level of 900 mg/day, and this dose was considered to be inappropriate. The recommended dose for the phase II/III clinical trial is thought to be 300 mg/day and 600 mg/day.
NIK-333（一种无环视黄醇）已被报道可预防根治性治疗后肝癌（HCC）患者的复发。本研究旨在确定 NIK-333 的最大耐受剂量、剂量限制性毒性（DLT）和药代动力学，该药以每天 300-900mg 的口服剂量给药。
在经皮局部消融或 HCC 手术后无癌症的患者中进行了这项研究。总日剂量作为单次剂量（单剂量阶段）给药，随后休息一周，然后在早餐和晚餐后等分为两份给药，连续 48 周（重复剂量阶段）。
在 300mg/天和 600mg/天剂量水平的患者中，没有任何患者发生任何 DLT。在最终的 900mg/天剂量水平，9 名患者中有 3 名发生 3 级高血压作为 DLT。空腹和餐后状态下的最大药物浓度（Cmax）和 log（Cmax）值没有显著差异。在重复剂量阶段，在任何剂量队列中，NIK-333 给药的起始和第 24 周之间，在 0-6 小时的血药浓度时间曲线下面积（AUC0-6）或 Cmax 均无显著差异。NIK-333 口服给药，每天剂量高达 600mg，连续 48 周时耐受性良好。
在 900mg/天的剂量水平下，高血压被认为是 DLT，这一剂量被认为是不合适的。认为 II/III 期临床试验的推荐剂量为 300mg/天和 600mg/天。
