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IntraOmmaya compartmental radioimmunotherapy using 131I-omburtamab-pharmacokinetic modeling to optimize therapeutic index.

Authors
  • Yerrabelli, Rahul S1, 2
  • He, Ping3
  • Fung, Edward K4, 5
  • Kramer, Kim1
  • Zanzonico, Pat B4
  • Humm, John L4
  • Guo, Hongfen1
  • Pandit-Taskar, Neeta6
  • Larson, Steven M6
  • Cheung, Nai-Kong V7
  • 1 Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
  • 2 Carle Illinois College of Medicine, University of Illinois at Urbana-Champaign, 807 South Wright Street, Suite 320, Champaign, IL, 61820, USA.
  • 3 Renaissance School of Medicine, Stony Brook University, 101 Nicolls Road, Stony Brook, NY, 11794, USA.
  • 4 Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
  • 5 Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA.
  • 6 Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
  • 7 Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. [email protected]
Type
Published Article
Journal
European Journal of Nuclear Medicine
Publisher
Springer-Verlag
Publication Date
Apr 01, 2021
Volume
48
Issue
4
Pages
1166–1177
Identifiers
DOI: 10.1007/s00259-020-05050-z
PMID: 33047248
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. 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)]. 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%. 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. ClinicalTrials.gov , NCT00089245.

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