Clinical Research, Drug Development Division, Sumitomo Dainippon Pharma Co., Ltd., Tokyo, Japan.
Clinical Research, Drug Development Division, Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan.
Pharmacol Res Perspect. 2021 Oct;9(5):e00874. doi: 10.1002/prp2.874.
This study examined the safety, tolerability, and pharmacokinetics (PK) of napabucasin in healthy Asian and non-Asian participants and investigated the potential for QT/QTc interval prolongation. This five-part (A-E) study proceeded in a stepwise manner, unless stopping criteria were met. Parts A-D were randomized, double-blind, placebo-controlled, and included healthy Asian male and female and non-Asian male participants. PK parameters were measured following single-dose napabucasin (80-1200 mg) in the fasted or fed state (Part D). Potential QT/QTc interval prolongation was assessed using digital 12-lead electrocardiogram (Parts B and C). Part E was open-label, and examined the PK of single-dose napabucasin (240-720 mg) in healthy non-Asian males. Safety and tolerability were measured in Parts A-E. Changes from baseline in the Fridericia-corrected QT interval (ΔQTcF) and other electrocardiogram parameters were analyzed using a linear mixed-effects model. Napabucasin was well-tolerated across the study (n = 70), and no serious adverse events or significant safety issues were reported when administered with or without food. The most frequent treatment-emergent adverse events were diarrhea and abdominal pain, and these were mild in severity. No prolongation of the QTcF interval was reported following single-dose napabucasin (240-1200 mg) and changes in other cardiac parameters were negligible. The PK profile of napabucasin was consistent with earlier studies. Single-dose napabucasin was tolerated in healthy male and female participants, and no significant safety (including no QTcF prolongation) or tolerability issues were identified, irrespective of food intake. Clinical studies of napabucasin in advanced cancers are ongoing.
这项研究旨在评估纳巴卡森（napabucasin）在健康亚洲和非亚洲参与者中的安全性、耐受性和药代动力学（PK），并研究其是否会导致 QT/QTc 间期延长。这项五部分（A-E）的研究逐步进行，除非达到停止标准。A 至 D 部分为随机、双盲、安慰剂对照研究，纳入了健康的亚洲男性和女性以及非亚洲男性参与者。在禁食或进食状态下（D 部分）给予参与者单次剂量纳巴卡森（80-1200mg）后，测量 PK 参数。使用数字 12 导联心电图（B 部分和 C 部分）评估潜在的 QT/QTc 间期延长。E 部分为开放标签研究，考察了健康非亚洲男性单次剂量纳巴卡森（240-720mg）的 PK。A-E 部分均评估安全性和耐受性。使用线性混合效应模型分析 Fridericia 校正 QT 间期（ΔQTcF）和其他心电图参数的基线变化。纳巴卡森在整个研究中耐受性良好（n=70），无论是否与食物同服，均未报告严重不良事件或显著安全性问题。最常见的治疗后不良事件为腹泻和腹痛，且均为轻度。单次剂量纳巴卡森（240-1200mg）给药后未报告 QTcF 间期延长，其他心脏参数的变化可忽略不计。纳巴卡森的 PK 特征与早期研究一致。单次剂量纳巴卡森在健康男性和女性参与者中耐受良好，无论是否进食，均未发现明显的安全性（包括 QTcF 间期延长）或耐受性问题。纳巴卡森在晚期癌症中的临床研究正在进行中。
