Oncology Department, iOnctura BV, Amsterdam, The Netherlands.
Chemical and Preclinical Safety Merck KGaA, Merck Healthcare KGaA, Darmstadt, Germany.
Int J Toxicol. 2023 Dec;42(6):515-534. doi: 10.1177/10915818231200419. Epub 2023 Sep 4.
Roginolisib (IOA-244) is a novel, non-ATP competitive phosphoinositide-3-kinase (PI3K) delta inhibitor that regulates Akt/mTOR signaling. Roginolisib was administered once daily to rats and dogs in dose-range finding (DRF) and 4-week GLP toxicology studies. Free plasma levels of roginolisib exceeded the cellular target engagement IC for PI3Kδ for ≥12 hours at doses of 5 mg/kg, the IC for PI3Kβ for ≥2 hours at doses ≥15 mg/kg, and the IC for PI3Kα for ≥2 hours at dose levels ≥45 mg/kg. Toxicity in rats occurred at doses ≥100 mg/kg. In dogs, we observed dose-dependent skin and gastrointestinal toxicity and doses ≥30 mg/kg had a greater incidence of mortality. Lymphoid tissue toxicity occurred in both species. Toxicities in dogs observed at the ≥15 mg/kg dose, affecting the digestive mucosa, liver, and skin, cleared after treatment cessation. Doses ≤75 mg/kg were tolerated in rats and the no-observed-adverse-effect-level (NOAEL) in rats was 15 mg/kg. Due to mainly epithelial lesions of the skin at 5 mg/kg and necrotizing damage of the intestinal epithelia at ≥15 mg/kg, no NOAEL was determined in dogs. However, the adverse effects observed in dogs at 5 mg/kg were considered monitorable and reversible in patients with advanced malignancies. Furthermore, the PK profile subsequently proved to be a decisive factor for achieving selective PI3Kδ inhibition without the toxicities observed in dogs. As the result of the unique PK profile of roginolisib, patients were able to take daily roginolisib without dose modification and showed pharmacodynamic PI3Kδ inhibition over several months without gastrointestinal or dermatologic toxicities.
罗格列利司（IOA-244）是一种新型的非 ATP 竞争性磷酸肌醇-3-激酶（PI3K）δ抑制剂，可调节 Akt/mTOR 信号通路。罗格列利司在剂量探索（DRF）和 4 周 GLP 毒理学研究中，每天一次给予大鼠和犬。在 5mg/kg 的剂量下，罗格列利司的游离血浆水平超过了 PI3Kδ的细胞靶标结合 IC，持续时间超过 12 小时；在 15mg/kg 及以上剂量下，PI3Kβ的 IC 持续时间超过 2 小时；在 45mg/kg 及以上剂量下，PI3Kα的 IC 持续时间超过 2 小时。在 100mg/kg 及以上剂量下，大鼠出现毒性。在犬中，我们观察到剂量依赖性的皮肤和胃肠道毒性，并且≥30mg/kg 的剂量有更高的死亡率。淋巴组织毒性在两种物种中均发生。在≥15mg/kg 剂量下观察到的犬毒性，影响消化黏膜、肝脏和皮肤，在治疗停止后可清除。在大鼠中，≤75mg/kg 的剂量可耐受，大鼠的无观察到不良效应水平（NOAEL）为 15mg/kg。由于 5mg/kg 时主要出现皮肤上皮病变，15mg/kg 及以上时出现肠上皮坏死损伤，因此在犬中未确定 NOAEL。然而，在 5mg/kg 时观察到的犬的不良反应被认为在晚期恶性肿瘤患者中是可监测和可逆的。此外，罗格列利司的 PK 特征随后被证明是实现选择性 PI3Kδ抑制而不出现犬中观察到的毒性的决定性因素。由于罗格列利司独特的 PK 特征，患者能够无需剂量调整而每日服用罗格列利司，并在数月内显示出药效学的 PI3Kδ抑制作用，而无胃肠道或皮肤毒性。
