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PURPOSE: Radioimmunotherapy (RIT) delivered through the cerebrospinal fluid (CSF) has been shown to be a safe and promising treatment for leptomeningeal metastases. Pharmacokinetic models for intra-Ommaya anti-GD2 monoclonal antibody (131)I-3F8 have been proposed to improve therapeutic effect while minimizing radiation toxicity. In this study, we now apply pharmacokinetic modeling to intra-Ommaya (131)I-omburtamab (8H9), an anti-B7-H3 antibody which has shown promise in RIT of leptomeningeal metastases. METHODS: Serial CSF samples were collected and radioassayed from 61 patients undergoing a total of 177 intra-Ommaya administrations of (131)I-omburtamab for leptomeningeal malignancy. A two-compartment pharmacokinetic model with 12 differential equations was constructed and fitted to the radioactivity measurements of CSF samples collected from patients. The model was used to improve anti-tumor dose while reducing off-target toxicity. Mathematical endpoints were (a) the area under the concentration curve (AUC) of the tumor-bound antibody, AUC[C(IAR)(t)], (b) the AUC of the unbound “harmful” antibody, AUC[C(IA)(t)], and (c) the therapeutic index, AUC[C(IAR)(t)]÷AUC[C(IA)(t)]. RESULTS: The model fit CSF radioactivity data well (mean R=96.4%). The median immunoreactivity of (131)I-omburtamab matched literature values at 69.1%. Off-target toxicity (AUC[C(IA)(t)]) was predicted to increase more quickly than AUC[C(IAR)(t)] as a function of (131)I-omburtamab dose, but the balance of therapeutic index and AUC[C(IAR)(t)] remained favorable over a broad range of administered doses (0.48–1.40mg or 881–2592MBq). While anti-tumor dose and therapeutic index increased with antigen density, the optimal administered dose did not. Dose fractionization into two separate injections increased therapeutic index by 38%, and splitting into 5 injections by 82%. Increasing antibody immunoreactivity to 100% only increased therapeutic index by 17.5%. CONCLUSION: The 2-compartmental pharmacokinetic model when applied to intra-Ommaya (131)I-omburtamab yielded both intuitive and non-intuitive therapeutic predictions. The potential advantage of further dose fractionization warrants clinical validation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00089245