Title | IntraOmmaya compartmental radioimmunotherapy using I-omburtamab-pharmacokinetic modeling to optimize therapeutic index. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Yerrabelli RS, He P, Fung EK, Kramer K, Zanzonico PB, Humm JL, Guo H, Pandit-Taskar N, Larson SM, Cheung N-KV |
Journal | Eur J Nucl Med Mol Imaging |
Volume | 48 |
Issue | 4 |
Pagination | 1166-1177 |
Date Published | 2021 04 |
ISSN | 1619-7089 |
Keywords | Antibodies, Monoclonal, Murine-Derived, Humans, Iodine Radioisotopes, Radioimmunotherapy, Therapeutic Index |
Abstract | 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 I-3F8 have been proposed to improve therapeutic effect while minimizing radiation toxicity. In this study, we now apply pharmacokinetic modeling to intraOmmaya I-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 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(t)], (b) the AUC of the unbound "harmful" antibody, AUC [C(t)], and (c) the therapeutic index, AUC [C(t)] ÷ AUC [C(t)]. RESULTS: The model fit CSF radioactivity data well (mean R = 96.4%). The median immunoreactivity of I-omburtamab matched literature values at 69.1%. Off-target toxicity (AUC [C(t)]) was predicted to increase more quickly than AUC [C(t)] as a function of I-omburtamab dose, but the balance of therapeutic index and AUC [C(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 I-omburtamab yielded both intuitive and nonintuitive therapeutic predictions. The potential advantage of further dose fractionization warrants clinical validation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT00089245. |
DOI | 10.1007/s00259-020-05050-z |
Alternate Journal | Eur J Nucl Med Mol Imaging |
PubMed ID | 33047248 |
PubMed Central ID | PMC8279045 |
Grant List | P30 CA008748 / CA / NCI NIH HHS / United States |