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

Background and Objective Lu-177-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 Lu-177-Dotatate a co-infusion of amino acids (AA) is administered, resulting in a decrease in tubular renal reabsorption of Lu-177-Dotatate. This study aimed to quantify the impact of AA co-infusion on the pharmacokinetics of Lu-177-Dotatate in cancer patients and to evaluate its relationship with toxicity during the first treatment cycle (C1). Methods 7.4 GBq of Lu-177-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 Lu-177-Dotatate. Radioactivity-time data (n = 346) were analyzed using NONMEM (R) (version 7.2.0). Results Lu-177-Dotatate pharmacokinetics was best described by a three-compartment model with first-order elimination. AA co-infusion had a significant effect ('fixed effect') on Lu-177-Dotatate pharmacokinetics, with a mean value of 1.5-fold (95% confidence interval 1.03-1.97) increase in the elimination rate constant (k(10)) 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 k(10) 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 k(10) value lower than 0.85. This variability in AA effect contributed to the variability in Lu-177-Dotatate plasma exposure (area under the concentration-time curve from time zero to Day 15 for C1 [AUC(Day15)]) that correlated with lymphopenia observed at Day 15 (p = 0.004). Conclusions A substantial effect of AA co-infusion on Lu-177-Dotatate pharmacokinetics was shown but was associated with high IIV, contributing to IIV in hematological toxicity.