Department of Pharmacokinetics and Pharmacodynamics, Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
Cancer Chemother Pharmacol. 2012 Apr;69(4):1071-8. doi: 10.1007/s00280-011-1807-5. Epub 2011 Dec 28.
MFGR1877A is a human IgG1 monoclonal antibody that binds to fibroblast growth factor receptor 3 (FGFR3) and is being investigated as a potential therapy for relapsed/refractory FGFR3+ multiple myeloma. The purpose of these studies was to characterize the pharmacokinetics (PK) of MFGR1877A in mouse, rat, and monkey and predict its human PK and efficacious dose.
PK of MFGR1877A was determined in athymic nude mice, Sprague-Dawley rats and cynomolgus monkeys after administration of single intravenous doses. Human PK profiles were projected from monkey PK profiles using a species-invariant time method, and human population PK parameters were estimated using a non-linear, two-compartment model comprising specific (target-mediated) and non-specific clearance pathways. The anti-tumor efficacy in mice bearing human tumor xenografts was used in conjunction with inhibitory activity in cell proliferation assays and human PK projections to estimate clinical efficacious dose.
The PK of MFGR1877A in mice was non-linear in the dose range of 1-50 mg/kg, while in rats and monkeys, PK was non-linear in the dose range of 1-10 mg/kg and linear at doses ≥ 10 mg/kg. The predicted non-specific clearance range in humans was 2.6-4.4 mL/day/kg. Doses ranging from 2 to 3 mg/kg weekly to 6-10 mg/kg every 4 weeks were predicted to achieve the target exposure in ≥ 90% of multiple myeloma patients.
The predicted non-specific clearance of MFGR1877A in humans is similar to typical human IgG1 antibodies and will be verified in a Phase 1 study. The projected human efficacious dose and regimen appear to be achievable in patients.
MFGR1877A 是一种人源 IgG1 单克隆抗体，可与成纤维细胞生长因子受体 3（FGFR3）结合，目前正在研究作为复发性/难治性 FGFR3+多发性骨髓瘤的潜在治疗方法。本研究的目的是表征 MFGR1877A 在小鼠、大鼠和猴子中的药代动力学（PK），并预测其在人体中的 PK 和有效剂量。
在单次静脉给药后，在裸鼠、Sprague-Dawley 大鼠和食蟹猴中测定 MFGR1877A 的 PK。使用种属不变时间法从猴 PK 谱中预测人体 PK 谱，并使用包含特异性（靶向介导）和非特异性清除途径的非线性两室模型估算人体群体 PK 参数。用人源肿瘤异种移植小鼠的抗肿瘤疗效，结合细胞增殖测定中的抑制活性和人体 PK 预测，估算临床有效剂量。
MFGR1877A 在小鼠中的 PK 呈非线性，剂量范围为 1-50mg/kg，而在大鼠和猴子中，PK 呈非线性，剂量范围为 1-10mg/kg，剂量≥10mg/kg 呈线性。在人体中预测的非特异性清除率范围为 2.6-4.4mL/天/kg。每周 2-3mg/kg 至每 4 周 6-10mg/kg 的剂量预计可使≥90%的多发性骨髓瘤患者达到目标暴露。
在人体中预测的 MFGR1877A 非特异性清除率与典型的人源 IgG1 抗体相似，将在 I 期研究中得到验证。预测的人体有效剂量和方案在患者中似乎是可行的。
