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Eur J Nucl Med Mol Imaging. 2011 Feb;38(2):334-42. doi: 10.1007/s00259-010-1633-8. Epub 2010 Oct 9.

Two-compartment model of radioimmunotherapy delivered through cerebrospinal fluid.

Author information

  • 1Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 USA. [corrected]

Erratum in

  • Eur J Nucl Med Mol Imaging. 2011 Feb;38(2):410.

Abstract

PURPOSE:

Radioimmunotherapy (RIT) using (131)I-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 (131)I-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[C(IAR)]), (2) that of the unbound antibody AUC[C(IA)], and (3) their therapeutic ratio (AUC[C(IAR)]/AUC[C(IA)]).

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 (131)I-3F8 from 10% to 90% increased both (AUC[C(IAR)]) and therapeutic ratio ([AUC[C(IAR)]/AUC[C(IA)]] by 7.4 fold, (2) When extrapolated to the clinical setting, the model predicted that if (131)I-3F8 could be split into 4 doses of 1.4 mg each and given at ≥24 hours apart, an antibody affinity of K(D) 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.

PMID:
20936407
[PubMed - indexed for MEDLINE]
PMCID:
PMC3278084
Free PMC Article

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