Evaluation of the Interaction of Amino Acid Infusion on 177Lu-Dotatate Pharmacokinetics in Patients with Gastroenteropancreatic Neuroendocrine Tumors.

Abstract

BACKGROUND AND OBJECTIVE:

177Lu-Dotatate is a radio-labeled analog of somatostatin used in the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. In order to prevent nephrotoxic effects of 177Lu-Dotatate a co-infusion of amino acids (AA) is administered, resulting in a decrease in tubular renal reabsorption of 177Lu-Dotatate. This study aimed to quantify the impact of AA co-infusion on the pharmacokinetics of 177Lu-Dotatate in cancer patients and to evaluate its relationship with toxicity during the first treatment cycle (C1).

METHODS:

7.4 GBq of 177Lu-Dotatate was administered to 42 patients over a 30-min intravenous infusion. Infusion of AA started 2 h before and continued for 6 h after the infusion of 177Lu-Dotatate. Radioactivity-time data (n = 346) were analyzed using NONMEM® (version 7.2.0).

RESULTS:

177Lu-Dotatate pharmacokinetics was best described by a three-compartment model with first-order elimination. AA co-infusion had a significant effect ('fixed effect') on 177Lu-Dotatate pharmacokinetics, with a mean value of 1.5-fold (95% confidence interval 1.03-1.97) increase in the elimination rate constant (k10) from 0.204 to 0.306 h-1, but this AA co-infusion effect was associated with a large inter-individual variability (IIV) of 104%. The individual k10 values increased during concomitant AA infusion by a factor ranging from 1.01 to 21.3 for 27 patients, whereas the opposite effect was observed in 15 patients (range 0.36-0.99) of whom seven had a k10 value lower than 0.85. This variability in AA effect contributed to the variability in 177Lu-Dotatate plasma exposure (area under the concentration-time curve from time zero to Day 15 for C1 [AUCDay15]) that correlated with lymphopenia observed at Day 15 (p = 0.004).

CONCLUSIONS:

A substantial effect of AA co-infusion on 177Lu-Dotatate pharmacokinetics was shown but was associated with high IIV, contributing to IIV in hematological toxicity.

• Authors: Alicja Puszkiel, Mathilde Bauriaud-Mallet, Roxane Bourgeois, Lawrence Dierickx, Frédéric Courbon, Etienne Chatelut
• Journal: Clinical pharmacokinetics (Clin Pharmacokinet) Vol. 58 Issue 2 Pg. 213-222 (02 2019) ISSN: 1179-1926 [Electronic] Switzerland
• PMID: 29736841 (Publication Type: Clinical Trial, Journal Article)

Chemical References

• Amino Acids
• Antineoplastic Agents
• Organometallic Compounds
• lutetium Lu 177 dotatate
• Octreotide

Topics

• Adult
• Aged
• Aged, 80 and over
• Amino Acids (administration & dosage)
• Antineoplastic Agents (adverse effects, blood, pharmacokinetics)
• Female
• Humans
• Infusions, Intravenous
• Intestinal Neoplasms (metabolism)
• Kidney (drug effects)
• Lymphocyte Count
• Male
• Middle Aged
• Models, Biological
• Neuroendocrine Tumors (metabolism)
• Octreotide (adverse effects, analogs & derivatives, blood, pharmacokinetics)
• Organometallic Compounds (adverse effects, blood, pharmacokinetics)
• Pancreatic Neoplasms (metabolism)
• Stomach Neoplasms (metabolism)