Population pharmacokinetic analysis of phase 1 bemarituzumab data to support phase 2 gastroesophageal adenocarcinoma FIG
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ORIGINAL ARTICLE
Population pharmacokinetic analysis of phase 1 bemarituzumab data to support phase 2 gastroesophageal adenocarcinoma FIGHT trial Hong Xiang1 · Lucy Liu2 · Yuying Gao2 · Ago Ahene1 · Monica Macal1,3 · Amy W. Hsu1,4 · Lyndah Dreiling1 · Helen Collins1 Received: 2 April 2020 / Accepted: 6 September 2020 © The Author(s) 2020
Abstract Purpose 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 (Ctrough) for an anti-fibroblast growth factor receptor 2b antibody, bemarituzumab. Methods 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 Ctrough 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. Results 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 Ctrough 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 Ctrough on Day 15 in 98% of patients with 96% maintaining the target at steady state, which was confirmed in the FIGHT trial. Conclusion A projected dose and schedule to achieve the target Ctrough was validated in phase 1 of the FIGHT trial which supported selection of the phase 2 dose and schedule for bemarituzumab. Keywords Bemarituzumab · Anti-fibroblast growth factor receptor 2b · Population PK analysis · Target-mediated clearance · Dose selection · Gastric and gastroesophageal junction adenocarcinoma
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00280-020-04139-4) contains supplementary material, which is available to authorized users. * Hong Xiang [email protected] 1
Five Prime Therapeutics, Inc., 111 Oyster Point Blvd, South San Francisco, CA 94080, USA
2
Shanghai Qiangshi Information Technology Co., Ltd, Shanghai, China
3
Present Address: TRex Bio, Inc., South San Francisco, CA, USA
4
Present Address: Merck and Co., South San Francisco, CA, USA
Gastric and gastroesophageal junction adenocarcinoma (GEA) represents the fourth most common cancer worldwide and is a highly lethal disease, with 5-year overall survival (OS) rates below 33% in the United States (US) [1–3]. Chemotherapy as standard first-line treatment has demonstrated an imp
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