Single vial kit formulation of DOTATATE for preparation of<sup>177</sup>Lu-labeled therapeutic radiopharmaceutical at hospital radiopharmacy

Mukherjee, Archana; Lohar, Sharad P.; Dash, Ashutosh; Sarma, Haladhar Dev; Samuel, Grace; Korde, Aruna

doi:10.1002/jlcr.3267

Cited by 5 publications

(3 citation statements)

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“…177 Lu-DOTATOC, 177 Lu-DOTATATE), requires the use of a stabilizer (e.g. L-ascorbic acid, gentisic acid) in order to inhibit peptide autoradiolysis (LUTATHERA n.d.; Mukherjee et al 2015; Liu et al 2003; Dash 2015; Esser 2006; Schuchardt 2013). The stability studies of 161 Tb-DOTATOC and 177 Lu-DOTATOC were performed with and without addition of L-ascorbic acid.…”

Section: Resultsmentioning

confidence: 99%

Production and characterization of no-carrier-added 161Tb as an alternative to the clinically-applied 177Lu for radionuclide therapy

Gracheva

Müller

Talip

et al. 2019

EJNMMI radiopharm. chem.

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Background 161 Tb is an interesting radionuclide for cancer treatment, showing similar decay characteristics and chemical behavior to clinically-employed 177 Lu. The therapeutic effect of 161 Tb, however, may be enhanced due to the co-emission of a larger number of conversion and Auger electrons as compared to 177 Lu. The aim of this study was to produce 161 Tb from enriched 160 Gd targets in quantity and quality sufficient for first application in patients. Methods No-carrier-added 161 Tb was produced by neutron irradiation of enriched 160 Gd targets at nuclear research reactors. The 161 Tb purification method was developed with the use of cation exchange (Sykam resin) and extraction chromatography (LN3 resin), respectively. The resultant product ( 161 TbCl 3 ) was characterized and the 161 Tb purity compared with commercial 177 LuCl 3 . The purity of the final product ( 161 TbCl 3 ) was analyzed by means of γ-ray spectrometry (radionuclidic purity) and radio TLC (radiochemical purity). The radiolabeling yield of 161 Tb-DOTA was assessed over a two-week period post processing in order to observe the quality change of the obtained 161 Tb towards future clinical application. To understand how the possible drug products (peptides radiolabeled with 161 Tb) vary with time, stability of the clinically-applied somatostatin analogue DOTATOC, radiolabeled with 161 Tb, was investigated over a 24-h period. The radiolytic stability experiments were compared to those performed with 177 Lu-DOTATOC in order to investigate the possible influence of conversion and Auger electrons of 161 Tb on peptide disintegration. Results Irradiations of enriched 160 Gd targets yielded 6–20 GBq 161 Tb. The final product was obtained at an activity concentration of 11–21 MBq/μL with ≥99% radionuclidic and radiochemical purity. The DOTA chelator was radiolabeled with 161 Tb or 177 Lu at the molar activity deemed useful for clinical application, even at the two-week time point after end of chemical separation. DOTATOC, radiolabeled with either 161 Tb or 177 Lu, was stable over 24 h in the presence of a stabilizer. Conclusions In this study, it was shown that 161 Tb can be produced in hig...

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Section: Resultsmentioning

confidence: 99%

Production and characterization of no-carrier-added 161Tb as an alternative to the clinically-applied 177Lu for radionuclide therapy

Gracheva

Müller

Talip

et al. 2019

EJNMMI radiopharm. chem.

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“…Предотвращение свободнорадикального окисления аскорбиновая кислота реализует за счет способности акцептировать активные формы кислорода в водной фазе и восстанавливать радикалы жирорастворимых антиоксидантов [79]. Эффективность аскорбиновой кислоты в качестве радиопротектора была продемонстрирована при синтезе РФЛП на основе 177 Lu [80,81]. В работе [82] показано, что 0,1 г/мл аскорбиновой кислоты в препарате [ 177 Lu]Lu-DOTA-[Pro 1 ,Tyr 4 ]-бомбезин с активностью 600 МБк/мл достаточно для поддержания РХЧ на приемлемом уровне (≥98 %) в течение 7 суток и при комнатной температуре.…”

Section: поиск и разработка новых лекарственных средств Research and ...unclassified

Selection and Use of Antioxidants-radioprotectors in the Composition of Therapeutic Radiopharmaceuticals (Review)

Pavlenko,

Larenkov,

Mitrofanov

2023

Razrabotka i registraciâ lekarstvennyh sredstv

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Introduction. The use of radiopharmaceuticals for targeted radionuclide therapy (TRT), the efficacy of which was established during clinical trials, is safe and effective for various pathological conditions, including cancer. The main feature of therapeutic radiopharmaceuticals (RPs) is the use of β–- and α-emitting radionuclides (RNs) in the finished dosage form (FD). Among the radionuclides used for radionuclide therapy, lutetium-177 is currently one of the most popular in clinical practice because of its chemical and nuclear characteristics. The list of RPs based on lutetium-177 is constantly expanding, and Lutathera® ([177Lu]Lu-DOTA-TATE) and Pluvicto™ ([177Lu]Lu-PSMA-617) have been approved for clinical use in several countries.Text. Because of the high activity of RNs in a single dose of therapeutic RPs (up to 8 GBq in a monodose for 177Lu), ionizing radiation of the used RNs leads to a decrease in RPs quality owing to radiolytic degradation of the vector molecule. This leads to a decreased specific accumulation of radioactivity in the foci of pathology, reduced therapeutic effect, and potentially increases the risk of radiotoxicity to non-target organs and tissues. The degree and intensity of radiolytic degradation of the vector molecule and, consequently, the shelf life of RPs depend on many factors, among which the activity concentration of the radionuclide in the preparation, its half-life, and the energy of the emitted particles are the most important. To suppress the effects of radiolysis, various excipients with antioxidant (radioprotective) properties were introduced into the compositions of the finished dosage forms. Among the substances studied, the most popular were gentisic acid, ascorbic acid, and ethanol. In this work, the advantages and disadvantages of various antioxidants and their combinations used in therapeutic RPs were considered in lutetium-177 preparations.Conclusion. Selection of the optimal composition of the dosage form is an urgent task, as it will ensure high-quality RPs both at the time of preparation and during the shelf life and delivery to the end user, which will greatly facilitate the use and centralized supply of therapeutic RPs. The necessity of creating a unified approach for the selection of antioxidants at the pharmaceutical development stage of radiopharmaceuticals is shown. For this purpose, an approach combining studies of radical reaction kinetics with studies of radiation-chemical yields of radiolysis products under identical or maximally similar conditions with subsequent verification of the stability of RPs dosage form seems to be very promising and has proven to be effective. In contrast, the empirical approach, which implies the selection of radioprotectors based on a direct study of their influence on the preservation of the level of radiochemical purity, is suboptimal because of the high market value of both radionuclides and non-radioactive precursors.

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“…Ascorbic acid has been proposed to be particularly useful as a buffer agent and radiolytic stabilizer simultaneously for the synthesis of metal-based radiopharmaceuticals [ 27 , 28 ]. The effectiveness of ascorbic acid as a radical scavenger has been demonstrated in the synthesis of 177 Lu-radiopharmaceuticals used in clinical practice [ 29 , 30 , 31 ]. At the same time, the use of ascorbic acid in the composition of radiopharmaceuticals is associated with a number of difficulties, including stability, oxidation, and color change during synthesis (with heating) and during preparation storage [ 32 , 33 , 34 ], problems with quantitative analysis of the components of the reaction mixture and the final dosage form [ 35 , 36 ], and a decrease in radiochemical conversion during synthesis (in comparison with other buffer agents such as MES and ammonium acetate [ 37 ]).…”

Section: Introductionmentioning

confidence: 99%

Radiolysis-Associated Decrease in Radiochemical Purity of 177Lu-Radiopharmaceuticals and Comparison of the Effectiveness of Selected Quenchers against This Process

et al. 2023

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The radiolytic degradation of vector molecules is a major factor affecting the shelf life of therapeutic radiopharmaceuticals. The development of time-stable dosage forms of radiopharmaceuticals is the key to their successful implementation in clinical practice. Using [177Lu]Lu-PSMA-617 molecule as an example, the time dependence of the change in radiochemical purity (RCP, %) under radiolysis conditions was studied. The dependence of [177Lu]Lu-PSMA-617 radiolysis on parameters such as time, radionuclide activity, buffer agent concentration, precursor amount, and preparation volume was evaluated. It was shown that the absorbed dose was the dominant factor influencing the RCP. The RCP value is inversely proportional to the absorbed dose in the [177Lu]Lu-PSMA-617 preparation and has an exponential dependence. The lutetium-177 dose factor ψ (Gy·mL·MBq−1) and PSMA-617 concentration-dependent dose constant κ (Gy−1) were evaluated for absorbed dose estimation via computer modeling, chemical dosimetry, and radiochemical purity monitoring under various conditions. The further refinement and application of the dependencies found can be useful for predicting the RCP value at the stage of optimizing the composition of the finished dosage form of therapeutic radiopharmaceuticals. The influence of the buffer agent (sodium acetate) concentration on [177Lu]Lu-PSMA-617 radiolytic degradation was shown and should be considered both when developing a dosage form, and when comparing the results of independent studies. The effectiveness of the addition of various stabilizing agents, such as DMSA, cysteine, gentisic acid, vanillin, methionine, adenine, dobesilic acid, thymine, uracil, nicotinamide, meglumine, and mannitol, in suppressing the effects of radiolysis was evaluated.

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Single vial kit formulation of DOTATATE for preparation of¹⁷⁷Lu-labeled therapeutic radiopharmaceutical at hospital radiopharmacy

Cited by 5 publications

References 20 publications

Production and characterization of no-carrier-added 161Tb as an alternative to the clinically-applied 177Lu for radionuclide therapy

Production and characterization of no-carrier-added 161Tb as an alternative to the clinically-applied 177Lu for radionuclide therapy

Selection and Use of Antioxidants-radioprotectors in the Composition of Therapeutic Radiopharmaceuticals (Review)

Radiolysis-Associated Decrease in Radiochemical Purity of 177Lu-Radiopharmaceuticals and Comparison of the Effectiveness of Selected Quenchers against This Process

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Single vial kit formulation of DOTATATE for preparation of177Lu-labeled therapeutic radiopharmaceutical at hospital radiopharmacy

Cited by 5 publications

References 20 publications

Production and characterization of no-carrier-added 161Tb as an alternative to the clinically-applied 177Lu for radionuclide therapy

Production and characterization of no-carrier-added 161Tb as an alternative to the clinically-applied 177Lu for radionuclide therapy

Selection and Use of Antioxidants-radioprotectors in the Composition of Therapeutic Radiopharmaceuticals (Review)

Radiolysis-Associated Decrease in Radiochemical Purity of 177Lu-Radiopharmaceuticals and Comparison of the Effectiveness of Selected Quenchers against This Process

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Single vial kit formulation of DOTATATE for preparation of¹⁷⁷Lu-labeled therapeutic radiopharmaceutical at hospital radiopharmacy