Early Oncology Development and Clinical Research, Pfizer Inc., 10777 Science Center Drive, San Diego, CA, 92121, USA.
Clinical Pharmacology/Pharmacometrics, Pfizer Essential Health Research and Development, Pfizer Inc, 300 Technology Square, Cambridge, MA, 02140, USA.
Cancer Chemother Pharmacol. 2019 Jul;84(1):83-92. doi: 10.1007/s00280-019-03850-1. Epub 2019 May 3.
PF-05280014 is a biosimilar to trastuzumab (Herceptin). Following demonstration of pharmacokinetic (PK) similarity in healthy volunteers, a comparative clinical study in patients with HER2-positive metastatic breast cancer (mBC) compared the efficacy, safety and immunogenicity of PF-05280014 and trastuzumab sourced from the EU (trastuzumab-EU), both with paclitaxel.
Population PK of PF-05280014 and trastuzumab-EU was evaluated.
Overall, 702 patients were treated: PF-05280014 (n = 349) and trastuzumab-EU (n = 353). Peak-and-trough serum drug concentration samples were collected (selected doses) following repeated intravenous administration of PF-05280014 or trastuzumab-EU. Population PK analysis was performed with drug concentration-time data to cycle 17 for each compound, using nonlinear mixed effect modeling. Potential baseline covariates (circulating HER2 concentrations, body weight, Japanese race, Eastern Cooperative Oncology Group status, number of metastatic sites and antidrug antibody status) were evaluated. Concentration-time data of PF-05280014 and trastuzumab-EU were adequately described by a two-compartment model with first-order elimination, with inter-individual variability (IIV) on clearance (CL), volumes of distribution in central compartment (V) and peripheral compartments, and intercompartment clearance. Similar estimated PK parameters and IIV were obtained for both treatments. For PF-05280014 and trastuzumab-EU, baseline body weight was an influential covariate on CL and V; the magnitude was comparable between treatments. PK was consistent between the limited number of Japanese and non-Japanese patients for both compounds.
PF-05280014 and trastuzumab-EU had similar PK parameters and influential PK covariates in patients with HER2-positive mBC. These results provided further evidence in patients for PK similarity between PF-05280014 and trastuzumab-EU.
ClinicalTrials.gov, NCT01989676.
PF-05280014 是曲妥珠单抗（赫赛汀）的生物类似药。在健康志愿者中证明了药代动力学（PK）相似性后，一项比较性临床试验在 HER2 阳性转移性乳腺癌（mBC）患者中比较了 PF-05280014 与源自欧盟的曲妥珠单抗（曲妥珠单抗-EU）联合紫杉醇的疗效、安全性和免疫原性。
评估了 PF-05280014 和曲妥珠单抗-EU 的群体 PK。
总体而言，共 702 例患者接受了治疗：PF-05280014（n=349）和曲妥珠单抗-EU（n=353）。在接受 PF-05280014 或曲妥珠单抗-EU 重复静脉给药后，采集了（选定剂量）达峰和谷值血清药物浓度样本。使用非线性混合效应模型，对每种化合物的第 17 个周期的药物浓度-时间数据进行了群体 PK 分析。评估了潜在的基线协变量（循环 HER2 浓度、体重、日本种族、东部合作肿瘤学组状态、转移部位数量和抗药物抗体状态）。PF-05280014 和曲妥珠单抗-EU 的浓度-时间数据通过具有一级消除的两室模型得到充分描述，个体间变异（IIV）存在于清除率（CL）、中央隔室（V）和外周隔室的分布容积以及隔室间清除率上。两种治疗方法均获得了相似的估计 PK 参数和 IIV。对于 PF-05280014 和曲妥珠单抗-EU，基线体重是 CL 和 V 的一个有影响的协变量；两种治疗方法之间的程度相当。对于两种化合物，日本和非日本患者的数量有限，PK 是一致的。
PF-05280014 和曲妥珠单抗-EU 在 HER2 阳性 mBC 患者中具有相似的 PK 参数和有影响的 PK 协变量。这些结果为患者提供了 PF-05280014 和曲妥珠单抗-EU 之间 PK 相似性的进一步证据。
ClinicalTrials.gov，NCT01989676。
