介绍
膝骨关节炎（OA）是一种常见的疼痛性疾病。关节内 (IA) 皮质类固醇注射经常用于治疗膝关节疼痛。 Lorecivivint (LOR) 是一种新型 IA cdc2 样激酶 (CLK)/双特异性酪氨酸磷酸化调节激酶 (DYRK) 抑制剂，被认为可以调节 Wnt 和炎症通路，与安慰剂相比，它看起来很安全，并且证明患者报告的结果有所改善。虽然 LOR 被建议单独使用，但在临床实践中，提供者可能会在与 IA 皮质类固醇接近的时间施用 LOR。这项开放标签、平行组、健康志愿者研究评估了 IA LOR 和间隔 7 天给药的曲安奈德 (TCA) 之间潜在的短期安全性、耐受性和药代动力学 (PK) 相互作用。
方法
健康志愿者被随机分配至治疗序列 1（IA 40 mg TCA，随后 IA 0.07 mg LOR）或治疗序列 2（IA 0.07 mg LOR，随后 IA 40 mg TCA）。治疗中出现的不良事件 (TEAE) 按“时期”进行分类，时期 1 跨越从第一次注射到第二次注射，时期 2 跨越从第二次注射到研究结束。在注射前和注射后 22 天评估血浆 PK，以评估 PK 治疗相互作用。
结果
40 名入组参与者中有 11 名（27.5%）报告了总共 18 次 TEAE，并且没有发生严重不良事件。治疗序列 1 报告了 13 例 TEAE，治疗序列 2 报告了 5 例 TEAE，在第 1 和第 2 时期之间的分布类似。在所有参与者和所有时间点，血浆 LOR 浓度均低于定量限 (0.100 ng/mL)。 TCA 的几何平均浓度和 PK 参数在治疗序列之间相似。
结论
没有观察到安全信号。在任一治疗序列中均没有可量化的 LOR 血浆浓度。 TCA 的 PK 不受先前 LOR 注射的影响。这些结果表明，在近距离内对 LOR 和 TCA 进行 IA 给药不太可能造成安全问题。
试用注册
ClinicalTrials.gov 标识符，NCT04598542。
"点击查看英文标题和摘要"
Safety, Tolerability, and Pharmacokinetics of Same-Knee Intra-Articular Injection of Corticosteroid and Lorecivivint Within 7 Days: An Open-Label, Randomized, Parallel-Arm Study
Introduction
Knee osteoarthritis (OA) is a common painful disorder. Intra-articular (IA) corticosteroid injections are frequently prescribed to treat knee pain. Lorecivivint (LOR), a novel IA cdc2-Like Kinase (CLK)/Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase (DYRK) inhibitor thought to modulate Wnt and inflammatory pathways, has appeared safe and demonstrated improved patient-reported outcomes compared with placebo. While LOR is proposed for stand-alone use, in clinical practice, providers might administer LOR in close time proximity to IA corticosteroid. This open-label, parallel-arm, healthy volunteer study assessed potential short-term safety, tolerability and pharmacokinetic (PK) interactions between IA LOR and triamcinolone acetonide (TCA) administered 7 days apart.
Methods
Healthy volunteers were randomized to Treatment Sequence 1 (IA 40 mg TCA followed by IA 0.07 mg LOR) or Treatment Sequence 2 (IA 0.07 mg LOR followed by IA 40 mg TCA). Treatment-emergent adverse events (TEAEs) were categorized by “epoch”, with epoch 1 spanning from first until second injection, and epoch 2 spanning from second injection until end of study. Plasma PK was assessed pre injection and out to 22 days after to assess PK treatment interaction.
Results
A total of 18 TEAEs were reported by 11 (27.5%) of 40 enrolled participants, and there were no serious adverse events. Thirteen TEAEs were reported in Treatment Sequence 1 and five in Treatment Sequence 2, similarly distributed between epochs 1 and 2. In all participants and at all time points, plasma LOR concentrations were below the limit of quantification (0.100 ng/mL). Geometric mean concentrations and PK parameters for TCA were similar between treatment sequences.
Conclusion
No safety signals were observed. There were no quantifiable plasma concentrations of LOR in either Treatment Sequence. The PK of TCA was unaffected by previous LOR injection. These results suggest that IA administration of LOR and TCA in close time proximity is unlikely to pose a safety concern.
Trial Registration
ClinicalTrials.gov identifier, NCT04598542.
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