Two-compartment model of radioimmunotherapy delivered through cerebrospinal fluid
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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.
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]).
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.
This model predicted that immunoreactivity, affinity and optimal scheduling of antibody injections were crucial in improving therapeutic index.
KeywordsPharmacokinetics Radioimmunotherapy Optimization 3F8 Intra-Ommaya Cerebrospinal fluid
Supported in part by grants from the National Institutes of Health CA106450, Robert Steel Foundation, Hope Street Kids, Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, Ludwig Center for Cancer Immunotherapy, and the Experimental Research Center of MSKCC. We want to thank Dr. Bingmei Fu of City College of the City University of New York for her critical review of the manuscript. Our thanks to Drs. Jorge Carasquillo and Neeta Pandit-Taskar of MSKCC for their administration of intraOmmaya 131I-3F8, and to Dr. Irene Cheung for critical review of the manuscript. N-K.V. Cheung was named as the inventor of antibody 3F8, which was assigned to Memorial-Sloan Kettering Cancer Center. 3F8 was licensed by Memorial-Sloan Kettering Cancer Center to United Therapeutics, Inc. United Therapeutics did not sponsor any of the laboratory or clinical research reported in these studies. The other authors disclosed no potential conflicts of interest.
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