Yamamura Naotoshi, Takakusa Hideo, Asano Daigo, Watanabe Kyoko, Shibaya Yukari, Yamanaka Ryo, Fusegawa Keiichi, Kanda Akira, Nagase Hiroyuki, Takaishi Kiyosumi, Koizumi Makoto, Takeshima Yasuhiro, Matsuo Masafumi
Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
Research & Innovation Promotion Department, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
Nucleosides Nucleotides Nucleic Acids. 2024 Aug 10:1-17. doi: 10.1080/15257770.2024.2389545.
The pharmacokinetics and tissue distribution of renadirsen sodium, a dystrophin exon-skipping phosphorothioate-modified antisense oligonucleotide with 2'-,4'--ethylene-bridged nucleic acid (ENA), after subcutaneous or intravenous administration to cynomolgus monkeys were investigated. The plasma concentration of renadirsen after subcutaneous administration at 1, 3, and 10 mg/kg increased with the dose. The absolute bioavailability at 3 mg/kg after subcutaneous administration was calculated as 88.6%, and the time to reach maximum plasma concentration of renadirsen was within 4 h, indicating the efficient and rapid absorption following subcutaneous administration. The exposure of muscle tissues to renadirsen was found to increase with repeated dosing at 6 mg/kg, and higher exposure was observed in the diaphragm and heart than in the quadriceps femoris and anterior tibialis muscles. Renadirsen achieved more exon 45-skipped dystrophin mRNA in the diaphragm and heart than in the quadriceps femoris and anterior tibialis muscles. Renadirsen also showed a cumulative skipping effect in a repeated-dose study. The findings on exon 45-skipped dystrophin mRNA in these muscle tissues were consistent with the concentration of renadirsen in these tissues. Because it is not feasible to directly evaluate drug concentration and exon skipping in the heart and diaphragm in humans, the pharmacokinetics and pharmacodynamics of renadirsen in these tissues in monkeys are crucial for the design and interpretation of clinical settings.
研究了雷纳地森钠（一种具有2',4'-乙烯桥连核酸（ENA）的抗肌萎缩蛋白外显子跳跃硫代磷酸酯修饰反义寡核苷酸）在食蟹猴皮下或静脉给药后的药代动力学和组织分布。皮下给予1、3和10mg/kg剂量的雷纳地森后，其血浆浓度随剂量增加而升高。皮下给予3mg/kg剂量后的绝对生物利用度计算为88.6%，雷纳地森达到最大血浆浓度的时间在4小时内，表明皮下给药后吸收高效且迅速。发现肌肉组织对雷纳地森的暴露量随6mg/kg重复给药而增加，且在膈肌和心脏中的暴露量高于股四头肌和胫前肌。与股四头肌和胫前肌相比，雷纳地森在膈肌和心脏中实现了更多外显子45跳跃的抗肌萎缩蛋白mRNA。在重复给药研究中，雷纳地森还表现出累积跳跃效应。这些肌肉组织中外显子45跳跃的抗肌萎缩蛋白mRNA的研究结果与这些组织中雷纳地森的浓度一致。由于直接评估人体心脏和膈肌中的药物浓度和外显子跳跃是不可行的，因此雷纳地森在猴这些组织中的药代动力学和药效学对于临床研究的设计和解释至关重要。
