Department of Pharmacologie, Institut Claudius-Regaud, Institut Universitaire du Cancer Toulouse - Oncopole; CRCT, Cancer Research Center of Toulouse, Inserm U1037, Université Paul Sabatier, 1 avenue Irène Joliot-Curie F-31059 Toulouse, France.
Department of Medical Imaging, Institut Universitaire du Cancer Toulouse - Oncopole, Toulouse, France.
Curr Radiopharm. 2022;15(2):164-172. doi: 10.2174/1874471015666211228123525.
Lu-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.
This study aimed to quantify the impact of two types of AA cocktails on the pharmacokinetics and toxicity of Lu-Dotatate.
Four injections of 7400 MBq Lu-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.
1,678 Lu-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 Lu-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®.
Unlike Primene®, Lysakare® does not increase Lu-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.
Lu-Dotatate 用于治疗生长抑素受体阳性不可切除的进展性胃肠胰神经内分泌肿瘤。同时输注氨基酸 (AA) 以预防肾毒性。
本研究旨在定量评估两种 AA 鸡尾酒对 Lu-Dotatate 药代动力学和毒性的影响。
每位患者接受 4 次 7400MBq Lu-Dotatate 注射，一种是使用 Primene® 10%（含 20 种 AA，赖氨酸 22g，精氨酸 16.8g），另一种是 Lysakare®（含 25g 赖氨酸和 25g 精氨酸）。每个周期采集 9 个血样。放射性时间数据采用 NONMEM（版本 7.4.1）基于群体模型进行分析。每个周期后评估肾毒性和血液学毒性。
从 83 例连续接受 Primene®（n=45 例）或 Lysakare®（n=36 例）治疗的患者中分析了 1678 个 Lu-Dotatate 血浆浓度-时间数据。群体药代动力学分析表明，与 Lysakare®相比，Primene®显著增加了 Lu-Dotatate 的消除率常数。Primene®还显著降低了 Lutathera®的血浆暴露（AUC）34%，而 Lysakare®则增加了 7%。两种情况下均无肾毒性。淋巴细胞减少与 AUC 显著相关（p=0.021），Lysakare®组的毒性有增加趋势。
与 Primene®不同，Lysakare®不会增加 Lu-Dotatate 的消除。这种差异与 AUC 显著相关。AUC 具有较高的个体间变异性，但个体内变异性较低，这可能对治疗调整具有重要的临床意义。
