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

• Published in: European journal of nuclear medicine and molecular imaging Vol. 30; no. 4; pp. 510 - 518
• Main Authors: Jamar, François, Barone, Raffaella, Mathieu, Isabelle, Walrand, Stéphan, Labar, Daniel, Carlier, Pascal, de Camps, Joëlle, Schran, Horst, Chen, TianLing, Smith, M Charles, Bouterfa, Hakim, Valkema, Roelf, Krenning, Eric P, Kvols, Larry K, Pauwels, Stanislas
• Format: Journal Article
• Language: English
• Published: Germany Springer Nature B.V 01.04.2003
• Subjects: Adult; Aged; Amino Acids - administration & dosage; Amino Acids - adverse effects; Arginine - administration & dosage; Cohort Studies; Cross-Over Studies; Dizziness - etiology; Drug Combinations; Female; Humans; Infusions, Intravenous; Kidney - drug effects; Kidney - metabolism; Lysine - administration & dosage; Male; Metabolic Clearance Rate; Middle Aged; Neuroendocrine Tumors - diagnostic imaging; Neuroendocrine Tumors - metabolism; Octreotide - adverse effects; Octreotide - analogs & derivatives; Octreotide - blood; Octreotide - pharmacokinetics; Octreotide - urine; Organ Specificity; Radiation Dosage; Radiation Injuries - etiology; Radiation-Protective Agents - administration & dosage; Radiation-Protective Agents - adverse effects; Radiometry - methods; Radiopharmaceuticals - pharmacokinetics; Tissue Distribution; Tomography, Emission-Computed; Vomiting - etiology; Yttrium Radioisotopes - adverse effects; Yttrium Radioisotopes - blood; Yttrium Radioisotopes - pharmacokinetics; Yttrium Radioisotopes - urine
• ISSN: 1619-7070; 1619-7089
• DOI: 10.1007/s00259-003-1117-1

The pharmacokinetics and dosimetry of (86)Y-DOTA(0)- d-Phe(1)-Tyr(3)-octreotide ((86)Y-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 (86)Y-SMT487 and PET scans were obtained at 4, 24 and 48 h p.i. Absorbed doses to tissues were computed using the MIRD3 method. (86)Y-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 (86)Y-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 (90)Y-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.