Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, 35 Gatehouse Drive, Boston, MA, 02451, USA.
Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Cambridge, UK.
Clin Pharmacokinet. 2019 May;58(5):615-625. doi: 10.1007/s40262-018-0714-x.
Olaparib is a first-in-class potent oral poly(ADP-ribose) polymerase inhibitor.
The aims of this analysis were to establish an integrated population pharmacokinetic (PK) model of olaparib in patients with solid tumors and to bridge the PK of olaparib between capsule and tablet formulations.
The population PK model was developed using plasma concentration data from 659 patients in 11 phase I, II, and III studies of olaparib tablets/capsules monotherapy. Relative bioavailability between the tablet and capsule formulations was estimated and the relative exposure between olaparib tablet and capsule therapeutic doses was further assessed.
The concentration-time profile was described using a two-compartment model with sequential zero- and first-order absorption and first-order elimination for both capsules and tablets with different absorption parameters. Multiple-dose clearance compared with single-dose clearance was reduced by approximately 15% (auto-inhibition). Disease severity had an impact on olaparib clearance, and tablet strength had an impact on K. The olaparib geometric mean area under the curve (AUC) and maximal concentration (C) following a single 300 mg tablet were 42.1 μg h/mL and 5.8 μg/mL, respectively, and the steady-state geometric mean AUC and C following a 300 mg tablet twice daily were 49.0 μg h/mL and 7.7 μg/mL, respectively. The relative exposure (AUC) of the 300 mg tablet formulation is 13% higher than the 400 mg capsule formulation.
This analysis bridged the olaparib capsule and tablet formulation PK and provided key assessment to support the approval of the olaparib tablet formulation in patients with ovarian cancer, regardless of their BRCA mutation status.
奥拉帕利是一种首创的强效口服聚（ADP-核糖）聚合酶抑制剂。
本分析旨在建立奥拉帕利在实体瘤患者中的群体药代动力学（PK）模型，并桥接奥拉帕利胶囊和片剂制剂之间的 PK。
使用来自 11 项奥拉帕利片剂/胶囊单药治疗的 I、II 和 III 期研究中 659 名患者的血浆浓度数据，开发了群体 PK 模型。估计了片剂和胶囊制剂之间的相对生物利用度，并进一步评估了奥拉帕利片剂和胶囊治疗剂量之间的相对暴露量。
使用具有顺序零级和一级吸收以及胶囊和片剂均具有不同吸收参数的一级消除的两室模型描述浓度-时间曲线。与单次剂量清除相比，多次剂量清除减少了约 15%（自动抑制）。疾病严重程度对奥拉帕利清除率有影响，片剂强度对 K 有影响。单次 300mg 片剂后奥拉帕利的几何平均 AUC 和 C 分别为 42.1μg·h/mL 和 5.8μg/mL，每日两次 300mg 片剂后稳态几何平均 AUC 和 C 分别为 49.0μg·h/mL 和 7.7μg/mL。300mg 片剂制剂的相对暴露（AUC）比 400mg 胶囊制剂高 13%。
本分析桥接了奥拉帕利胶囊和片剂制剂的 PK，并提供了关键评估，支持批准奥拉帕利片剂制剂用于卵巢癌患者，无论其 BRCA 突变状态如何。
