Published in:
01-02-2019 | Original Research Article
Evaluation of the Interaction of Amino Acid Infusion on 177Lu-Dotatate Pharmacokinetics in Patients with Gastroenteropancreatic Neuroendocrine Tumors
Published in: Clinical Pharmacokinetics | Issue 2/2019
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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.