Purpose: The pharmacokinetics (PK) of an antibody in the brain is not fully understood, which becomes an obstacle for drug discovery in the brain. Previously we have reported that a humanized IgG antibody is cleared by cerebrospinal fluid (CSF) bulk flow after intracerebroventricular (ICV) administration. Here to understand the elimination in CSF and absorption into plasma after ICV dosing more deeply, novel PK model was developed.
Methods: A humanized IgG antibody were administered by ICV injection in rat to reveal the PK profile of IgG. CSF and plasma were collected in a time-sequential manner. Concentrations of IgG were measured by Gyrolab. PK analysis was performed using Phoenix WinNonlin and SAAM II software.
Results: The IgG in CSF was disappeared with a half-life of 47.9 min and a clearance of 29.0 mL/day/kg, and transferred totally into plasma within 24 hours, which suggests elimination by bulk flow. To reveal the relationship between elimination from CSF and absorption into plasma, PK model was developed with or without lag time. Simulation by PK model without lag time showed faster absorption compared to observation, which could not describe PK profile in plasma well. On the other hand PK model with lag time could describe the absorption phase well, which indicates that there is a time lag in the absorption from CSF and plasma.
Conclusion: Time lag was found in the absorption phase from CSF to plasma. A suggested PK model with lag time could describe the elimination of a humanized IgG from CSF and the absorption to plasma well.
Motohiro Kato– Chugai Pharmaceutical Co., Ltd.
Takako Sakamoto– Chugai Research Institute for Medical Science Inc.
Akiko Uno– Chugai Research Institute for Medical Science Inc.
Natsuko Komiyama– Chugai Research Institute for Medical Science Inc.
Yoshinobu Higuchi– Chugai Research Institute for Medical Science Inc.
Eiji Kaneko– Chugai Research Institute for Medical Science Inc.
Kazuhisa Ozeki– Chugai Pharmaceutical Co., Ltd.
Masaki Ishigai– Chugai Pharmaceutical Co., Ltd.