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. 2003 Apr;30(4):510-8. doi: 10.1007/s00259-003-1117-1. Epub 2003 Feb 12.

Abstract

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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Amino Acids
  • Drug Combinations
  • Radiation-Protective Agents
  • Radiopharmaceuticals
  • Yttrium Radioisotopes
  • Arginine
  • Lysine
  • Octreotide
  • Edotreotide