Development of a Compartmental Pharmacokinetic Model for Molecular Radiotherapy with 131I-CLR1404.

Sara Neira,Araceli Gago-Arias,Isabel Gónzalez-Crespo,Jacobo Guiu-Souto,Juan Pardo-Montero

doi:10.3390/pharmaceutics13091497

Abstract

Pharmacokinetic modeling of the radiopharmaceuticals used in molecular radiotherapy is an important step towards accurate radiation dosimetry of such therapies. In this paper, we present a pharmacokinetic model for CLR1404, a phospholipid ether analog that, labeled with 124I/131I, has emerged as a promising theranostic agent. We follow a systematic approach for the model construction based on a decoupling process applied to previously published experimental data, and using the goodness-of-fit, Sobol’s sensitivity analysis, and the Akaike Information Criterion to construct the optimal form of the model, investigate potential simplifications, and study factor prioritization. This methodology was applied to previously published experimental human time-activity curves for 9 organs. The resulting model consists of 17 compartments involved in the CLR1404 metabolism. Activity dynamics in most tissues are well described by a blood contribution plus a two-compartment system, describing fast and slow uptakes. The model can fit both clinical and pre-clinical kinetic data of 124I/131I. In addition, we have investigated how simple fits (exponential and biexponential) differ from the complete model. Such fits, despite providing a less accurate description of time-activity curves, may be a viable alternative when limited data is available in a practical case.

Highlights

The phospholipid ether analog CLR1404 (18-(p-iodophenyl)octadecyl phosphocholine) has emerged in the last years as an interesting compound for nuclear medicine applications.The derived radiopharmaceuticals 124 I- and 131 I-CLR1404 are of potential interest in molecular radiotherapy (MRT) applications as a theranostic duo
We relied on blood and urine activity data from [8], as such data were not reported by Besemer et al In the latter study [8], the biokinetics of the 131 I-CLR1404 was examined, and both blood and urine samples were collected over time for a patient cohort
The resulting fits were evaluated according to the value of the objective function and the AICc, from which the structure to be incorporated into the final model was selected

Summary

Introduction

The phospholipid ether analog CLR1404 (18-(p-iodophenyl)octadecyl phosphocholine) has emerged in the last years as an interesting compound for nuclear medicine applications.The derived radiopharmaceuticals 124 I- and 131 I-CLR1404 are of potential interest in molecular radiotherapy (MRT) applications as a theranostic duo. Several preclinical studies have demonstrated tumor growth suppression, high tumor and metastasis specificity, prolonged retention for a variety of cancer cell lines, and low healthy tissue toxicity [1,2,3,4,5,6]. Biokinetic compartmental models have been long employed for internal dosimetry calculations in nuclear medicine. These mathematical tools allow modeling the metabolic mechanisms of an administered radiopharmaceutical and to characterize its activity distribution in the body over time. They are an important tool for internal dosimetry in Pharmaceutics 2021, 13, 1497.

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