Millennium Pharmaceuticals, Inc., a Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited, 40 Landsdowne Street, Cambridge, MA, 02139, USA.
Departments of Hematology and Medical Oncology and Pharmacology, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
Clin Pharmacokinet. 2019 Apr;58(4):431-449. doi: 10.1007/s40262-018-0702-1.
Ixazomib, the first oral proteasome inhibitor, is approved in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. Ixazomib is a selective, potent, and reversible inhibitor of the 20S proteasome, and preferentially binds to and inhibits the β5 chymotrypsin-like proteolytic site. Ixazomib absorption is rapid, with a median time to reach maximum plasma concentration of approximately 1 h post-dose. Ixazomib pharmacokinetics (PK) are adequately described by a three-compartment model (terminal half-life of 9.5 days) with first-order linear absorption (oral bioavailability of 58%). Plasma exposures of ixazomib increase in a dose-proportional manner. A high-fat meal decreases both the rate and extent of ixazomib absorption, supporting administration on an empty stomach. Population PK analyses demonstrated that no dose adjustment is required based on age, body size/weight, race, sex, mild-to-moderate renal impairment, or mild hepatic impairment. Results from dedicated studies indicate that a reduced starting dose (from 4 to 3 mg) is appropriate for patients with severe renal impairment, end-stage renal disease requiring dialysis, or moderate-to-severe hepatic impairment. Non-cytochrome P450 (CYP)-mediated metabolism appears to be the major clearance mechanism for ixazomib. Drug-drug interaction studies have shown no meaningful effects of strong inhibitors of CYP3A on ixazomib PK; however, the strong inducer rifampin caused a clinically relevant reduction in ixazomib exposure, supporting the recommendation to avoid concomitant administration of ixazomib with strong CYP3A inducers. Exposure-response analyses of data from the phase III TOURMALINE-MM1 registrational study demonstrate a favorable benefit-risk profile for the approved dose and regimen of weekly ixazomib 4 mg on days 1, 8, and 15 of each 28-day cycle.
依沙佐米是首个口服蛋白酶体抑制剂，与来那度胺和地塞米松联合用于治疗至少接受过一次治疗的多发性骨髓瘤（MM）患者。依沙佐米是一种选择性、有效且可逆的 20S 蛋白酶体抑制剂，优先结合并抑制β5 糜蛋白酶样蛋白水解位点。依沙佐米吸收迅速，给药后约 1 小时达到最大血浆浓度的中位时间。依沙佐米药代动力学（PK）通过三房室模型得到充分描述（终末半衰期为 9.5 天），具有线性首过吸收（口服生物利用度为 58%）。依沙佐米的血浆暴露量呈剂量比例增加。高脂肪餐会降低依沙佐米的吸收速率和程度，支持空腹给药。群体 PK 分析表明，无需根据年龄、体型/体重、种族、性别、轻度至中度肾功能损害或轻度肝功能损害调整剂量。专门研究的结果表明，对于严重肾功能损害、需要透析的终末期肾病或中重度肝功能损害的患者，起始剂量（从 4 毫克降至 3 毫克）较低是合适的。非细胞色素 P450（CYP）介导的代谢似乎是依沙佐米清除的主要机制。药物相互作用研究表明，CYP3A 的强抑制剂对依沙佐米 PK 无明显影响；然而，强诱导剂利福平导致依沙佐米暴露量显著降低，支持避免依沙佐米与强 CYP3A 诱导剂同时给药的建议。来自 III 期 TOURMALINE-MM1 注册研究的数据暴露-反应分析表明，每周依沙佐米 4 毫克，第 1、8 和 15 天给药，每个 28 天周期 1 次的批准剂量和方案具有良好的获益风险比。
