Antigen Mass May Influence Trastuzumab Concentrations in Cerebrospinal Fluid After Intrathecal Administration

Area of Science:

• Neuro-oncology
• Pharmacokinetics
• Monoclonal Antibody Therapy

Background:

• Intravenous monoclonal antibodies achieve low central nervous system (CNS) concentrations, posing challenges for neuro-oncology, particularly HER2-overexpressing breast cancer with leptomeningeal carcinomatosis.
• Intrathecal (IT) trastuzumab administration shows promise in case reports, but optimal dosing lacks pharmacokinetic (PK) data.

Purpose of the Study:

• To characterize the population pharmacokinetics of trastuzumab following IT administration in patients with HER2-overexpressing breast cancer and leptomeningeal carcinomatosis.
• To describe the drug's disposition in cerebrospinal fluid (CSF) and serum and evaluate factors influencing its concentration.

Main Methods:

• A population PK analysis was conducted on data from 21 women in a phase I-II clinical trial receiving weekly IT trastuzumab for 8 weeks.
• CSF and serum samples were collected to measure trough concentrations.
• A target-mediated drug disposition model was used to predict CSF concentration fluctuations.

Main Results:

• Apparent volumes of distribution for serum (V1 = 3.25 L) and CSF (V2 = 0.644 L) were physiological.
• Estimated transfer from serum to CSF (k12 = 0.264 mg/day) was slow, while CSF to serum transfer was rapid (half-life = 2.2 days).
• A single 150 mg IT trastuzumab dose resulted in median mean residence times of 3.8 days in CSF and 15.6 days in serum.

Conclusions:

• Trastuzumab transfer from serum to CSF is limited following IT administration.
• The monoclonal antibody is rapidly cleared from the CSF into the serum.
• Survival without neurological relapse was not correlated with trastuzumab exposure in this study.