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86Y-DOTA0-d-Phe1-Tyr3-octreotide (SMT487)—a phase 1 clinical study: pharmacokinetics, biodistribution and renal protective effect of different regimens of amino acid co-infusion

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Abstract

The pharmacokinetics and dosimetry of 86Y-DOTA0-d-Phe1-Tyr3-octreotide (86Y-SMT487) were evaluated in a phase I positron emission tomography (PET) study of 24 patients with somatostatin receptor-positive neuroendocrine tumours. The effect of amino acid (AA) co-infusion on renal and tumour uptake was assessed in a cross-over randomised setting. Five regimens were tested: no infusion, 4-h infusion of 120 g mixed AA (26.4 g l-lysine + l-arginine), 4 h l-lysine (50 g), 10 h 240 g mixed AA (52.8 g l-lysine + l-arginine) and 4 h Lys-Arg (25 g each). Comparisons were performed on an intra-patient basis. Infusions of AA started 0.5 h prior to injection of 86Y-SMT487 and PET scans were obtained at 4, 24 and 48 h p.i. Absorbed doses to tissues were computed using the MIRD3 method. 86Y-SMT487 displayed rapid plasma clearance and exclusive renal excretion; uptake was noted in kidneys, tumours, spleen and, to a lesser extent, liver. The 4-h mixed AA co-infusion significantly (P<0.05) reduced 86Y-SMT487 renal uptake by a mean of 21%. This protective effect was significant on the dosimetry data (3.3±1.3 vs 4.4±1.0 mGy/MBq; P<0.05) and was further enhanced upon prolonging the infusion to 10 h (2.1±0.4 vs 1.7±0.2 mGy/MBq; P<0.05). Infusion of Lys-Arg but not of l-lysine was more effective in reducing renal uptake than mixed AA. Infusion of AA did not result in reduced tumour uptake. The amount of 90Y-SMT487 (maximum allowed dose: MAD) that would result in a 23-Gy cut-off dose to kidneys was calculated for each study: MAD was higher with mixed AA co-infusion by a mean of 46% (10–114%, P<0.05 vs no infusion). In comparison with 4 h mixed AA, the MAD was higher by a mean of 23% (9–37%; P<0.05) with prolonged infusion and by a mean of 16% (2–28%; P<0.05) with Lys-Arg. We conclude that infusion of large amounts of AA reduces renal exposure during peptide-based radiotherapy and allows higher absorbed doses to tumours. The prolongation of the infusion from 4 to 10 h further enhances the protective effect on the kidneys.

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Acknowledgements

The expertise of Prof. C. Michel (Physics, PET Laboratory) and M. Cogneau (Nuclear Chemistry, PET Laboratory) was much appreciated. The authors thank P.P.M. Kooij (Erasmus MC, Rotterdam, Holland) for help in the dosimetry calculations.

Novartis Pharma Corp, East Hanover, N.J., financially supported this study.

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Authors and Affiliations

  1. Centre of Nuclear Medicine and Laboratory of Positron Emission Tomography, University of Louvain Medical School, Brussels and Louvain-la-Neuve, UCL 54.30, Avenue Hippocrate, 54, 1200, Brussels, Belgium

    François Jamar, Raffaella Barone, Isabelle Mathieu, Stéphan Walrand, Daniel Labar, Pascal Carlier, Joëlle De Camps & Stanislas Pauwels

  2. Novartis Pharma Corp., East Hanover, NJ, USA

    Horst Schran, TianLing Chen, M. Charles Smith & Hakim Bouterfa

  3. Department of Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands

    Roelf Valkema & Eric P. Krenning

  4. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL, USA

    Larry K. Kvols

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  1. François Jamar
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Correspondence to François Jamar.

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Jamar, F., Barone, R., Mathieu, I. et al. 86Y-DOTA0-d-Phe1-Tyr3-octreotide (SMT487)—a phase 1 clinical study: pharmacokinetics, biodistribution and renal protective effect of different regimens of amino acid co-infusion. Eur J Nucl Med Mol Imaging 30, 510–518 (2003). https://doi.org/10.1007/s00259-003-1117-1

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