IntraOmmaya compartmental radioimmunotherapy using (131)I-omburtamab-pharmacokinetic modeling to optimize therapeutic index Journal Article


Authors: Yerrabelli, R. S.; He, P.; Fung, E. K.; Kramer, K.; Zanzonico, P. B.; Humm, J. L.; Guo, H.; Pandit-Taskar, N.; Larson, S. M.; Cheung, N. K. V.
Article Title: IntraOmmaya compartmental radioimmunotherapy using (131)I-omburtamab-pharmacokinetic modeling to optimize 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 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 [CIAR(t)], (b) the AUC of the unbound “harmful” antibody, AUC [CIA(t)], and (c) the therapeutic index, AUC [CIAR(t)] ÷ AUC [CIA(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 [CIA(t)]) was predicted to increase more quickly than AUC [CIAR(t)] as a function of 131I-omburtamab dose, but the balance of therapeutic index and AUC [CIAR(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. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature.
Keywords: cerebrospinal fluid; neuroblastoma; radioimmunotherapy; pharmacokinetics; 131i-omburtamab
Journal Title: European Journal of Nuclear Medicine and Molecular Imaging
Volume: 48
Issue: 4
ISSN: 1619-7070
Publisher: Springer  
Date Published: 2021-04-01
Start Page: 1166
End Page: 1177
Language: English
DOI: 10.1007/s00259-020-05050-z
PUBMED: 33047248
PROVIDER: scopus
DOI/URL:
Notes: Article -- Export Date: 3 May 2021 -- Source: Scopus
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MSK Authors
  1. Nai-Kong Cheung
    565 Cheung
  2. Kim Kramer
    197 Kramer
  3. John Laurence Humm
    374 Humm
  4. Pat B Zanzonico
    295 Zanzonico
  5. Steven M Larson
    902 Larson
  6. Hong-Fen Guo
    51 Guo
  7. Edward Komin Fung
    10 Fung