Xiang Hong, Liu Lucy, Gao Yuying, Ahene Ago, Macal Monica, Hsu Amy W, Dreiling Lyndah, Collins Helen
Five Prime Therapeutics, Inc., 111 Oyster Point Blvd, South San Francisco, CA, 94080, USA.
Shanghai Qiangshi Information Technology Co., Ltd, Shanghai, China.
Cancer Chemother Pharmacol. 2020 Nov;86(5):595-606. doi: 10.1007/s00280-020-04139-4. Epub 2020 Sep 23.
To report population pharmacokinetic (PK) analysis of the phase 1 study (FPA144-001, NCT02318329) and to select a clinical dose and schedule that will achieve an empirical target trough concentration (C) for an anti-fibroblast growth factor receptor 2b antibody, bemarituzumab.
Nonlinear mixed-effect modeling was used to analyse PK data. In vitro binding affinity and receptor occupancy of bemarituzumab were determined. Simulation was conducted to estimate dose and schedule to achieve an empirical target C in a phase 2 trial (FIGHT, NCT03694522) for patients receiving first-line treatment combined with modified 5-fluourouracil, oxaliplatin and leucovorin (mFOLFOX6) for gastric and gastroesophageal junction adenocarcinoma.
Bemarituzumab PK is best described by a two-compartment model with parallel linear and nonlinear (Michaelis-Menten) elimination from the central compartment. Albumin, gender, and body weight were identified as the covariates on the linear clearance and/or volume of distribution in the central compartment, and no dose adjustment was warranted. An empirical target of bemarituzumab C of ≥ 60 µg/mL was projected to achieve > 95% receptor occupancy based on in vitro data. Fifteen mg/kg every 2 weeks, with a single dose of 7.5 mg/kg on Cycle 1 Day 8, was projected to achieve the target C on Day 15 in 98% of patients with 96% maintaining the target at steady state, which was confirmed in the FIGHT trial.
A projected dose and schedule to achieve the target C was validated in phase 1 of the FIGHT trial which supported selection of the phase 2 dose and schedule for bemarituzumab.
报告1期研究（FPA144-001，NCT02318329）的群体药代动力学（PK）分析，并选择一种临床剂量和给药方案，以达到抗成纤维细胞生长因子受体2b抗体bemarituzumab的经验性目标谷浓度（C）。
采用非线性混合效应模型分析PK数据。测定了bemarituzumab的体外结合亲和力和受体占有率。进行模拟以估计在2期试验（FIGHT，NCT03694522）中，接受一线治疗联合改良氟尿嘧啶、奥沙利铂和亚叶酸钙（mFOLFOX6）治疗胃和胃食管交界腺癌患者达到经验性目标C的剂量和给药方案。
bemarituzumab的PK最好用二室模型描述，中央室存在平行的线性和非线性（米氏）消除。白蛋白、性别和体重被确定为中央室线性清除率和/或分布容积的协变量，无需调整剂量。根据体外数据，预计bemarituzumab C的经验性目标≥60 μg/mL可实现>95%的受体占有率。预计每2周15 mg/kg，在第1周期第8天单剂量给予7.5 mg/kg，可使98%的患者在第15天达到目标C，96%的患者在稳态时维持目标C，这在FIGHT试验中得到了证实。
在FIGHT试验的1期验证了达到目标C的预计剂量和给药方案，这支持了bemarituzumab 2期剂量和给药方案的选择。
