Abstract 5633: Two-compartment pharmacokinetics model of radioimmunotherapy with 131I-3F8 directly administered into the cerebrospinal fluid

Abstract

Abstract Introduction Injection of 131I-3F8 directly into the cerebrospinal fluid (CSF) through an Ommaya reservoir is a safe form of radioimmunotherapy (RIT) treatment for leptomeningeal metastasis (JCO, 25:5465, 2007). Recently, we described a one-compartment pharmacokinetics model that showed good fitting to CSF sampling data from 6 patients (JNM 50:1324, 2009). We now describe an improved two-compartment model to take into account the ventricular reservoir before 131I-3F8 distribution into the subarachnoid space and to explore limiting factors that may significantly affect the efficacy of the therapy. Methods The distribution and binding of 131I-3F8 in the cerebral spinal fluid were modeled using a system of rate equations derived from the principle of mass conservation. The model was fitted to CSF sampling data from an expanded cohort of patients (39 injections in 25 patients). Three sets of criteria were used to examine the effect of each parameter on the efficacy of the treatment. These criteria were (1) the area under the radioactivity concentration curve of the bound antibody (AUC[CIAR]) (2) the unbound antibody AUC[CIA], and (3) their therapeutic ratio (AUC[CIAR]/AUC[CIA]). In addition to parameters tested in the previous model, immunoreactivity, tumor distribution, and nonspecific binding were also tested. Results The two-compartment model showed improved fitting to patient data when compared to the one compartment model (R=0.92±0.11 versus 0.77±0.21, p=0.005). Predictions from the one compartment model were confirmed. Furthermore, we made these new observations: (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) The presence of ≤ 5% tumor cells in the ventricles or ≤ 10% of nonspecific 131I-3F8 binding to normal tissues had no appreciable effect on the therapeutic ratio. When extrapolated to a 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 and immunoreactivity of 50% were adequate in order to deliver ≥10,000 Rad to tumor cells while keeping normal CSF exposure to <1,000 Rad. Conclusion The two compartment model of intra-ommaya radioimmunotherapy showed better fitting to patient data than the one-compartment model. This model predicted that immunoreactivity and affinity were crucial in improving therapeutic efficacy. Nevertheless, an optimal scheduling of antibody injections should permit highly favorable therapeutic ratio even with 4 nM affinities and suboptimal immunoreactivity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5633.