Sarah Cannon Research Institute at HealthONE, Denver, Colorado.
START San Antonio, San Antonio, Texas.
Clin Ther. 2024 Mar;46(3):228-238. doi: 10.1016/j.clinthera.2024.01.004. Epub 2024 Feb 28.
The poly (ADP-ribose) polymerase inhibitor niraparib is indicated as maintenance treatment in patients with certain subtypes of advanced ovarian cancer, and is being investigated in patients with other solid tumors. Niraparib is available in 100-mg capsules with a starting dosage of 200 or 300 mg/d. This study assessed the relative bioavailability (BA) and bioequivalence (BE) between a 1 × 300-mg tablet relative to 3 × 100-mg niraparib capsules. In addition, the food effect (FE) of a high-fat meal on the pharmacokinetic (PK) properties of tablet-formulated niraparib was investigated.
This was a US-based, 3-stage, open-label, multicenter, single-crossover, randomized-sequence study. Enrolled patients were 18 years and older, with histologically or cytologically confirmed advanced solid tumors (metastatic or local) and disease progression despite standard therapy. Patients were randomly assigned 1:1 to receive niraparib 1 × 300-mg tablet or 3 × 100-mg capsules in the BA and BE stages or 1 × 300-mg tablet in a fasted or fed (high-fat meal) state in the FE stage. Across all study stages, PK parameters were assessed for 7 days after each dose (tablet or capsule) or prandial state (fasted or fed). In the BA stage, patients crossed over to the other treatment after a 7-day washout period, which was extended to 14 days in the BE and FE stages. Tolerability was assessed for patients who received any amount of niraparib.
The BA-, BE-, and FE-evaluable populations comprised 23, 108, and 19 patients, respectively, who completed both treatment periods in each study stage, had sufficient concentration data to accurately estimate PK parameters without niraparib carryover, and did not experience disqualifying events. PK parameters were similar after dosing with tablet or capsule formulations; the 90% CIs of the geometric least square means for C, AUC, and AUC were within the 0.80 to 1.25 BE limits. In the FE stage, C, AUC, and AUC were 11%, 32%, and 28% higher, respectively, in the fed versus fasted state. The safety population included 29, 168, and 28 patients in the BA, BE, and FE stages, respectively, who received niraparib. No new safety signals were identified.
Niraparib tablets were found to be bioequivalent to capsules. A modest (≤32%) FE was observed with a high-fat meal, but was not considered to be clinically meaningful, given niraparib's PK variability.
gov identifier: NCT03329001. (Clin Ther. 2024;46:XXX-XXX) © 2024 Elsevier HS Journals, Inc.
聚（ADP-核糖）聚合酶抑制剂尼拉帕利被批准用于治疗某些特定类型的晚期卵巢癌患者的维持治疗，目前正在其他实体瘤患者中进行研究。尼拉帕利有 100 毫克胶囊，起始剂量为 200 毫克或 300 毫克/天。本研究评估了 1×300 毫克片剂相对于 3×100 毫克尼拉帕利胶囊的相对生物利用度（BA）和生物等效性（BE）。此外，还研究了高脂肪餐对片剂尼拉帕利的药代动力学（PK）特性的食物效应（FE）。
这是一项在美国进行的 3 期、开放标签、多中心、单交叉、随机序列研究。入组患者年龄为 18 岁及以上，组织学或细胞学证实有晚期实体肿瘤（转移性或局部），且标准治疗后疾病进展。患者按 1:1 随机分配接受尼拉帕利 1×300 毫克片剂或 3×100 毫克胶囊在 BA 和 BE 阶段，或在 FE 阶段空腹或进食（高脂肪餐）状态下接受 1×300 毫克片剂。在所有研究阶段，在每个剂量（片剂或胶囊）或餐前/餐后状态后 7 天评估 PK 参数。在 BA 阶段，患者在 7 天洗脱期后交叉到另一种治疗，在 BE 和 FE 阶段延长至 14 天。评估了接受任何剂量尼拉帕利的患者的耐受性。
BA、BE 和 FE 可评估人群分别包括 23、108 和 19 名患者，他们在每个研究阶段均完成了两个治疗期，有足够的浓度数据准确估计 PK 参数，且无尼拉帕利残留，并未发生导致淘汰的事件。片剂和胶囊制剂给药后 PK 参数相似；几何均数最小二乘均值的 90%置信区间（CI）在 0.80 至 1.25 的 BE 范围内。在 FE 阶段，与空腹相比，进食时 C、AUC 和 AUC 分别增加了 11%、32%和 28%。安全性人群分别包括 BA、BE 和 FE 阶段的 29、168 和 28 名患者，他们接受了尼拉帕利治疗。未发现新的安全性信号。
尼拉帕利片剂被发现与胶囊具有生物等效性。高脂肪餐观察到适度（≤32%）的食物效应，但鉴于尼拉帕利的 PK 变异性，认为这没有临床意义。
gov 标识符：NCT03329001。（临床治疗。2024；46：XXX-XXX）©2024 Elsevier HS 期刊，Inc.
