Delivery to the target site and adversities related to off-target exposure have made the road to clinical success and approval of antisense oligonucleotide (AON) therapies challenging. Various classes of AONs have distinct chemical features and pharmacological properties. Understanding the similarities and differences in pharmacokinetics (PKs) among AON classes is important to make future development more efficient and may facilitate regulatory guidance of AON development programs. For the class of 2'-O-methyl phosphorothioate (2OMe PS) RNA AONs, most nonclinical and clinical PK data available today are derived from development of exon skipping therapies for Duchenne muscular dystrophy (DMD). While some publications have featured PK aspects of these AONs, no comprehensive overview is available to date. This article presents a detailed review of absorption, distribution, metabolism, and excretion of 2OMe PS AONs, compiled from publicly available data and previously unpublished internal data on drisapersen and related exon skipping candidates in preclinical species and DMD patients. Considerations regarding drug-drug interactions, toxicokinetics, and pharmacodynamics are also discussed. From the data presented, the picture emerges of consistent PK properties within the 2OMe PS class, predictable behavior across species, and a considerable overlap with other single-stranded PS AONs. A level of detail on muscle as a target tissue is provided, which was not previously available. Furthermore, muscle biopsy samples taken in DMD clinical trials allowed confirmation of the applicability of interspecies scaling approaches commonly applied in the absence of clinical target tissue data.

中文翻译：

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2'-O-磷酸硫代磷酸甲酯反义寡核苷酸的药代动力学：从开发针对杜兴肌营养不良的外显子跳过疗法的经验。

递送至靶位和与脱靶暴露相关的逆境已为临床成功和批准反义寡核苷酸（AON）治疗铺平了道路。各种类型的AON具有不同的化学特征和药理特性。了解AON类之间的药代动力学（PK）的相似性和差异对于提高未来的开发效率和促进AON开发计划的监管指导很重要。对于2'-O-甲基硫代磷酸酯（2OMe PS）RNA AON，当今可用的大多数非临床和临床PK数据均来自针对杜氏肌营养不良症（DMD）的外显子跳过疗法的发展。尽管一些出版物已经介绍了这些AON的PK方面，但迄今为止尚无全面的概述。本文介绍了2OMe PS AON的吸收，分布，代谢和排泄的详细综述，该文献是根据公开可用的数据以及以前未发表的有关Drisapersen和相关外显子跳过者在临床前物种和DMD患者中的内部数据而汇编的。还讨论了有关药物相互作用，毒物动力学和药效学的注意事项。从提供的数据来看，图片展现出2OMe PS类中一致的PK特性，跨物种的可预测行为以及与其他单链PS AON的显着重叠。提供了有关肌肉作为目标组织的详细信息，而以前没有此信息。此外，