Two-compartment model of radioimmunotherapy delivered through cerebrospinal fluid

Abstract

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