Two-compartment model of radioimmunotherapy delivered through cerebrospinal fluid

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[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 ¹³¹I-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 ¹³¹I-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.