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IntraOmmaya compartmental radioimmunotherapy using 131I-omburtamab—pharmacokinetic modeling to optimize therapeutic index
- Source :
- European Journal of Nuclear Medicine and Molecular Imaging. 48:1166-1177
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
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.
- Subjects :
- medicine.medical_specialty
medicine.drug_class
business.industry
medicine.medical_treatment
Therapeutic effect
Urology
General Medicine
Monoclonal antibody
030218 nuclear medicine & medical imaging
03 medical and health sciences
0302 clinical medicine
Cerebrospinal fluid
Therapeutic index
Antigen
Pharmacokinetics
030220 oncology & carcinogenesis
Radioimmunotherapy
Toxicity
medicine
Radiology, Nuclear Medicine and imaging
business
Subjects
Details
- ISSN :
- 16197089 and 16197070
- Volume :
- 48
- Database :
- OpenAIRE
- Journal :
- European Journal of Nuclear Medicine and Molecular Imaging
- Accession number :
- edsair.doi...........a08890db81c976657e3c95323358cc41