Research Division, Chugai Pharmaceutical Co. Ltd., 1-135 Komakado, Gotemba-shi, Shizuoka, 412-8513, Japan.
Pharm Res. 2021 Apr;38(4):583-592. doi: 10.1007/s11095-021-03028-6. Epub 2021 Mar 29.
The aim of this study was to develop a useful antibody PK evaluation tool using a combination of cassette-dosing and microsampling in mice and monkeys in order to reduce the number of animals used.
Cetuximab, denosumab, infliximab, and a mixture of the three antibodies, i.e., cassette-dosing, were administered intravenously to cynomolgus monkeys, C57BL/6J mice, and homozygous human neonatal Fc-receptor transgenic (Tg32) mice. Mouse blood was collected from one animal continuously via the jugular vein at nine points.
In cynomolgus monkeys, infliximab showed faster elimination in the cassette-dosing group than in the single-dose group. Anti-drug antibody production was observed, but the PK parameters of the clearance and distribution volume were similar in both groups. In C57BL/6J and Tg32 mice, each of the plasma concentrations-time profiles after cassette-dosing were similar to those after single dosing. PK evaluation using a combination of cassette-dosing and microsampling in mice may reduce the number of mice used by approximately 90% compared with the conventional method.
The combination of antibody cassette-dosing and microsampling is a promising PK evaluation method as a high-throughput and reliable with reduced numbers of mice and cynomolgus monkeys.
本研究旨在开发一种使用组合式盒式给药和微采样的方法，用于小鼠和猴子中的抗体 PK 评估，以减少动物使用数量。
西妥昔单抗、地舒单抗、英夫利昔单抗和三种抗体混合物（即盒式给药）通过静脉内给予食蟹猴、C57BL/6J 小鼠和纯合人新生 Fc 受体转基因（Tg32）小鼠。从小鼠颈静脉连续采集一只动物的血液，共采集 9 个点。
在食蟹猴中，与单次剂量组相比，英夫利昔单抗在盒式给药组中表现出更快的消除。观察到抗药物抗体的产生，但清除率和分布容积的 PK 参数在两组中相似。在 C57BL/6J 和 Tg32 小鼠中，每个盒式给药后的血浆浓度-时间曲线与单次给药后相似。与传统方法相比，使用组合式盒式给药和微采样进行的小鼠 PK 评估可能将小鼠的使用数量减少约 90%。
抗体盒式给药和微采样的组合是一种有前途的 PK 评估方法，具有高通量、高可靠性，同时减少了小鼠和食蟹猴的使用数量。
