European Journal of Nuclear Medicine and Molecular Imaging

, Volume 38, Issue 2, pp 334–342

Two-compartment model of radioimmunotherapy delivered through cerebrospinal fluid

  • Ping He
  • Kim Kramer
  • Peter Smith-Jones
  • Pat Zanzonico
  • John Humm
  • Steven M. Larson
  • Nai-Kong V. Cheung
Original Article

DOI: 10.1007/s00259-010-1633-8

Cite this article as:
He, P., Kramer, K., Smith-Jones, P. et al. Eur J Nucl Med Mol Imaging (2011) 38: 334. doi:10.1007/s00259-010-1633-8

Abstract

Purpose

Radioimmunotherapy (RIT) using 131I-3F8 injected into cerebrospinal fluid (CSF) was a safe modality for the treatment of leptomeningeal metastases (JCO, 25:5465, 2007). A single-compartment pharmacokinetic model described previously (JNM 50:1324, 2009) showed good fitting to the CSF radioactivity data obtained from patients. We now describe a two-compartment model to account for the ventricular reservoir of 131I-3F8 and to identify limiting factors that may impact therapeutic ratio.

Methods

Each parameter was examined for its effects on (1) the area under the radioactivity concentration curve of the bound antibody (AUC[CIAR]), (2) that of the unbound antibody AUC[CIA], and (3) their therapeutic ratio (AUC[CIAR]/AUC[CIA]).

Results

Data fitting showed that CSF kBq/ml data fitted well using the two-compartment model (R = 0.95 ± 0.03). Correlations were substantially better when compared to the one-compartment model (R = 0.92 ± 0.11 versus 0.77 ± 0.21, p = 0.005). In addition, we made the following new predictions: (1) Increasing immunoreactivity of 131I-3F8 from 10% to 90% increased both (AUC[CIAR]) and therapeutic ratio ([AUC[CIAR]/AUC[CIA]] by 7.4 fold, (2) When extrapolated to the clinical setting, the model predicted that if 131I-3F8 could be split into 4 doses of 1.4 mg each and given at ≥24 hours apart, an antibody affinity of KD of 4 × 10-9 at 50% immunoreactivity were adequate in order to deliver ≥100 Gy to tumor cells while keeping normal CSF exposure to <10 Gy.

Conclusions

This model predicted that immunoreactivity, affinity and optimal scheduling of antibody injections were crucial in improving therapeutic index.

Keywords

PharmacokineticsRadioimmunotherapyOptimization3F8Intra-OmmayaCerebrospinal fluid

Supplementary material

259_2010_1633_MOESM1_ESM.docx (313 kb)
ESM 1(DOCX 312 kb)

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Ping He
    • 4
  • Kim Kramer
    • 1
  • Peter Smith-Jones
    • 2
  • Pat Zanzonico
    • 3
  • John Humm
    • 3
  • Steven M. Larson
    • 2
  • Nai-Kong V. Cheung
    • 1
  1. 1.Department of PediatricsMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  2. 2.Department of RadiologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  3. 3.Department of Medical PhysicsMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  4. 4.Department of Biomedical EngineeringJohns Hopkins UniversityBaltimoreUSA