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.
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.
Jamar
François
F
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. francois.jamar@mnuc.ucl.ac.be
Barone
Raffaella
R
Mathieu
Isabelle
I
Walrand
Stéphan
S
Labar
Daniel
D
Carlier
Pascal
P
de Camps
Joëlle
J
Schran
Horst
H
Chen
TianLing
T
Smith
M Charles
MC
Bouterfa
Hakim
H
Valkema
Roelf
R
Krenning
Eric P
EP
Kvols
Larry K
LK
Pauwels
Stanislas
S
D000328:Adult; D000368:Aged; D000596:Amino Acids / Q000008:administration & dosage* / Q000009:adverse effects; D001120:Arginine / Q000008:administration & dosage; D015331:Cohort Studies; D018592:Cross-Over Studies; D004244:Dizziness / Q000209:etiology; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D008239:Lysine / Q000008:administration & dosage; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000000981:diagnostic imaging / Q000378:metabolism*; D015282:Octreotide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D009928:Organ Specificity; D011829:Radiation Dosage; D011832:Radiation Injuries / Q000209:etiology; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000009:adverse effects; D011874:Radiometry / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D014839:Vomiting / Q000209:etiology; D015021:Yttrium Radioisotopes / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D000596:Amino Acids; D004338:Drug Combinations; D011837:Radiation-Protective Agents; D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; D001120:Arginine; D008239:Lysine; D015282:Octreotide; C106246:Edotreotide