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 intraOmmaya antiGD2 monoclonal antibody ¹³¹I-3F8 have been proposed to improve therapeutic effect while minimizing radiation toxicity. In this study, we now apply pharmacokinetic modeling to intraOmmaya ¹³¹I-omburtamab (8H9), an antiB7-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 intraOmmaya administrations of ¹³¹I-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 ¹³¹I-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 ¹³¹I-omburtamab dose, but the balance of therapeutic index and AUC [C_IAR(t)] remained favorable over a broad range of administered doses (0.48–1.40 mg or 881–2592 MBq). While antitumor 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 intraOmmaya ¹³¹I-omburtamab yielded both intuitive and nonintuitive therapeutic predictions. The potential advantage of further dose fractionization warrants clinical validation. Clinical trial registration ClinicalTrials.gov, NCT00089245.

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