Buil-Bruna Núria, Garrido María Jesús, Dehez Marion, Manon Amandine, Nguyen Thi Xuan Quyen, Gomez-Panzani Edda L, Trocóniz Iñaki F
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Irunlarrea 1, 31080, Pamplona, Spain.
Clinical Pharmacokinetics, Pharmacokinetics and Drug Metabolism, Ipsen Innovation, Les Ulis, France.
Clin Pharmacokinet. 2016 Apr;55(4):461-73. doi: 10.1007/s40262-015-0329-4.
Lanreotide Autogel (lanreotide Depot in the USA) has demonstrated anti-tumor activity and control of the symptoms associated with hormone hypersecretion in patients with neuroendocrine tumors. The objectives of this study were to describe the pharmacokinetics of lanreotide Autogel administered 4-weekly by deep subcutaneous injections of 60, 90, or 120 mg in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs), to quantify the magnitude of inter-patient variability (IPV), and to identify those patient characteristics that impact on pharmacokinetics.
Analyses were based on pooled data from clinical trials. A total of 1541 serum concentrations from 290 patients were analyzed simultaneously by the population approach using NONMEM version 7.2. Covariates evaluated included demographics, renal and hepatic function markers, and disease-related parameters.
Serum profiles were described by a one-compartment disposition model in which the absorption process was characterized by two parallel pathways following first- and zero-order kinetics. The estimated apparent volume of distribution was 18.3 L. The estimated apparent total serum clearance for a typical 74 kg patient was 513 L/day, representing a substantial difference in clearance in this population of patients with respect to healthy volunteers that could not be explained by any of the covariates tested. Body weight was the only covariate to show a statistically significant effect on the pharmacokinetic profile, but due to the overlap between the pharmacokinetic profiles of patients with lower or higher body weights the effect of body weight on clearance was not considered clinically relevant. The IPV was low for clearance (27%) and moderate to high for volume of distribution (150%) and the absorption constant (61%).
Using two mechanisms of absorption, the pharmacokinetics of lanreotide Autogel were well-described in patients with GEP-NET. None of the patient characteristics tested were of clinical relevance to potential dose adjustment in clinical practice.
兰瑞肽长效凝胶（在美国为兰瑞肽缓释剂）已在神经内分泌肿瘤患者中显示出抗肿瘤活性，并能控制与激素分泌过多相关的症状。本研究的目的是描述在胃肠胰神经内分泌肿瘤（GEP-NET）患者中每4周深部皮下注射60、90或120mg兰瑞肽长效凝胶后的药代动力学，量化患者间变异性（IPV）的大小，并确定影响药代动力学的患者特征。
分析基于临床试验的汇总数据。使用NONMEM 7.2版的群体方法同时分析了来自290例患者的总共1541个血清浓度。评估的协变量包括人口统计学、肾和肝功能标志物以及疾病相关参数。
血清曲线由单室处置模型描述，其中吸收过程由遵循一级和零级动力学的两条平行途径表征。估计的表观分布容积为18.3L。对于典型的74kg患者，估计的表观总血清清除率为513L/天，这表明该患者群体的清除率与健康志愿者相比存在显著差异，且无法通过所测试的任何协变量来解释。体重是唯一对药代动力学曲线有统计学显著影响的协变量，但由于体重较低或较高患者的药代动力学曲线存在重叠，因此体重对清除率的影响在临床上不被认为具有相关性。清除率的IPV较低（27%），分布容积（150%）和吸收常数（61%）的IPV为中度至高度。
采用两种吸收机制，兰瑞肽长效凝胶在GEP-NET患者中的药代动力学得到了很好的描述。所测试的患者特征均与临床实践中潜在的剂量调整无临床相关性。
