Pharmacometric Modeling and Simulation for Evaluation of Bioequivalence for Leuprolide Acetate Injection

项目总结摘要 与口服药物相比，长效注射剂(Lai)具有更好的疗效和耐受性。 以提高依从性和更稳定的药代动力学。然而，关于LAI的数据喜忧参半，其中一些 研究发现，它们更有效，更容易接受，而其他人的研究结果与此相反。一键 LAIS的优点是使用控释可以更容易地实现靶向治疗窗口 机制。然而，LAIS的主要缺点是个体间的差异过大。 药代动力学变异性。随着许多LAI配方即将失去专利， 仿制药的开发正在增加。生物等效性论证指南(BE) 仿制药产品和竞争者之间的关系需要明确的定义，以帮助仿制药的开发 莱氏产品。不幸的是，在LAI中存在巨大的个体间差异，这使得这些阈值 很难达到。醋酸亮丙瑞林(路普隆仓库)是一种常用的LAI；它价格昂贵，而且没有 通用配方。鲁普隆临床用于治疗子宫内膜异位症、子宫肌瘤、 性早熟和晚期前列腺癌的姑息治疗。醋酸亮丙瑞林是一种九肽 促性腺激素释放激素受体(GnRHR)激动剂，用于修改个人的激素谱。 具体地说，醋酸亮丙瑞林与垂体前叶的促性腺激素释放激素受体结合比促性腺激素释放激素更具亲和力 导致促黄体生成素(L H)和卵泡刺激素(FSH)的最初突然释放。然而， 随着时间的推移，服用醋酸亮丙瑞林会使GnRHR脱敏，减少黄体生成素和黄体生成素的释放 FSH，因此这些激素、雌二醇和睾酮的浓度在全身 发行量。这项建议的目标是使用Lupron作为原型LAI来开发药物计量学和 能够进行生物等效性评估的模拟方法。这项研究将从患者那里收集数据 正在接受路普隆的各种适应症治疗。基线黄体生成素和卵泡刺激素的变化将被用作 路普隆局部放电效应的标志物。将分析患者样本中Lupron的浓度(用于 药代动力学(PK)、促黄体生成素和卵泡刺激素、性腺类固醇(即睾酮和双氢睾酮 男性和绝经前女性的雌酮和雌二醇)，以及出生时的激素水平(用于 药效学(PD)评估)。行动的时间进程将被用作BE的标志。这项研究将 进行人口PK/PD建模和统计分析。这将开发和演示方法，以 便于根据预期响应的比较相似性对任何LAI代理进行统计BE评估 (Pd)，最终作为BE评估的基础。因此，利用现成的和频繁的 所使用的试剂Lupron将使生物等效PD方法学的开发成为可能，以帮助 确定基准监管决策的方法。

PROJECT SUMMARY ABSTRACT Long-acting injectables (LAIs) offer the promise of better efficacy and tolerability, compared to oral drugs due to improved adherence and more stable pharmacokinetics. However, data on LAIs has been mixed, with some studies finding that they are more effective and tolerable while others report findings to the contrary. One key advantage of LAIs is that a target therapeutic window can be more easily achieved using the controlled release mechanism. However, the central disadvantage of LAIs is the exceedingly large inter-individual pharmacokinetic variability. As numerous LAI formulations are going off-patent, opportunities for the development of generic medications are increasing. The guidelines to demonstrate bioequivalence (BE) between a generic product and a competitor require a clear definition to assist in the development of generic LAI products. Unfortunately, the presence of the large inter-individual variability in LAIs makes these thresholds difficult to attain. Leuprolide acetate (Lupron depot) is a frequently used LAI; it is expensive, and there is no generic formulation. Lupron is used clinically for treatment of endometriosis, uterine leiomyoma, central precocious puberty, and palliative treatment of advanced prostatic cancer. Leuprolide acetate is a nonapeptide gonadotropin-releasing hormone receptor (GnRHR) agonist, used to modify an individual's hormone profile. Specifically, leuprolide acetate binds to the GnRHR in the anterior pituitary with a greater affinity than GnRH causing an initial burst release of leutinizing hormone (LH) and follicle-stimulating hormone (FSH). However, over time, leuprolide acetate administration will desensitize the GnRHR, decreasing the release of LH and FSH, and therefore the concentrations of those hormones and estradiol and testosterone in systemic circulation. The objective of this proposal is to use Lupron as a prototypical LAI to develop pharmacometric and simulation methodology to enable bioequivalence assessment. This study will collect data from patients who are being treated with Lupron for a variety of indications. Changes in baseline LH and FSH will be used as markers for the PD effects of Lupron. Patient samples will be analyzed for concentrations of Lupron (for pharmacokinetic (PK) assessment), LH and FSH, gonadal steroids (i.e., testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females), and natal hormone levels (for pharmacodynamic (PD) assessment). Time course of action will be used as a marker of BE. This study will perform population PK/PD modeling and statistical analysis. This will develop and demonstrate methodology to facilitate statistical BE assessment of any LAI agents based upon comparative similarity of intended response (PD) which ultimately serves as the basis for BE evaluation. Thus, utilizing a readily available and frequently utilized agent, Lupron, will enable the development of bioequivalent PD methodology to aid in the process of defining the methodology for benchmark regulatory decisions.