Comparison of Two Types of Amino Acid Solutions on 177Lu-DotatatePharmacokinetics and Pharmacodynamics in Patients with Metastatic GastroenteropancreaticNeuroendocrine Tumors
Étienne Chatelut, Marie Lambert, Lawrence Dierickx, S. Brillouet, F. Courbon
Abstract
Background: 177Lu-Dotatate is used in the treatment of somatostatin-receptor-positive inoperable progressive gastroenteropancreatic neuroendocrine tumors. A co-infusion of amino acids (AAs) is administered to prevent renal toxicity. Objective: This study aimed to quantify the impact of two types of AA cocktails on the pharmacokinetics and toxicity of 177Lu-Dotatate. Method: Four injections of 7400 MBq 177Lu-Dotatate were given per patient with administration of either Primene® 10% (containing a cocktail of 20 AAs with 22g of Lysine and 16.8 g of Arginine) or Lysakare® (containing 25 g of Lysine and 25 g of Arginine). Nine blood samples were collected at each cycle. Radioactivity-time data were analyzed according to a population-based model using NONMEM (version 7.4.1). Renal and hematological toxicity was evaluated after each cycle. Result: 1,678 177Lu-Dotatate plasma concentrations versus time were analyzed from 83 consecutive patients with Primene® (n= 45 pts) or Lysakare® (n= 36 pts). Population pharmacokinetic analysis showed that Primene® significantly increased the elimination rate constant of 177Lu-Dotatate as opposed to Lysakare®. Primene® also significantly lowered Lutathera® plasma exposure (AUC) by 34%, whereas Lysakare® increased AUC by 7%. There was no renal toxicity in either case. Lymphopenia significantly correlated with AUC (p=0.021) with a trend towards higher toxicity with Lysakare®. Conclusions:: Unlike Primene®, Lysakare® does not increase 177Lu-Dotatate elimination. This difference is associated with a significant impact on AUC. The latter parameter has a high interpatient variability but a low intrapatient variability, which could have important clinical implications for treatment tailoring.