建立已获批准的 GLP-1 受体激动剂的细胞分析体外效力与临床有效浓度之间的关系。

IF 4.9 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Alessandro Boianelli, Pär Nordell, Joseph Earl, Jacqueline Naylor, David Hornigold, Rasmus Jansson Löfmark, Monika Sundqvist
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引用次数: 0

摘要

背景:胰高血糖素样肽-1 受体激动剂(GLP-1RAs)在治疗 2 型糖尿病(T2D)和肥胖症方面发挥着重要作用。对于这类分子的疗效与给药方案之间的关系已经进行了广泛的研究。然而,目前仍缺乏将体外数据转化为体内有效暴露的全面分析。研究方法我们收集了五种已获批准的 GLP-1RA 的临床药代动力学数据,以模拟暴露曲线,并将已公布的临床疗效终点(HbA1c 和体重)与在不同细胞检测中生成的内部体外药效值进行比较。此外,我们还研究了与目标覆盖率的相关性,目标覆盖率用稳态药物暴露与非结合效力、体重或 T2D 患者 HbA1c 降低率之间的比率表示。结果:我们发现,在没有任何血清白蛋白或使用卵清白蛋白的情况下进行的细胞检测所产生的体外药效数据与体内疗效的相关性最好。在内源性细胞系中或使用人血清白蛋白时产生的体外药效数据的残留变异性较大。对于不含白蛋白的人体受体检测,暴露量超过 100 倍的体外 EC50 会导致 HbA1c 降低 >1.5% 点,而降低 5% 的体重与高出约 3 倍的暴露量有关。卵清蛋白测定中也有类似的关系。结论总之,体外药效和体内药效之间的关系将有助于提高新 GLP-1RA 在发现和早期临床阶段的人体剂量预测和试验设计的信心。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Establishing a Relationship between In Vitro Potency in Cell-Based Assays and Clinical Efficacious Concentrations for Approved GLP-1 Receptor Agonists.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) play an important role in the treatment of type 2 diabetes (T2D) and obesity. The relationship between efficacy and dosing regimen has been studied extensively for this class of molecules. However, a comprehensive analysis of the translation of in vitro data to in vivo efficacious exposure is still lacking. Methods: We collected clinical pharmacokinetics for five approved GLP-1RAs to enable the simulation of exposure profiles and compared published clinical efficacy endpoints (HbA1c and body weight) with in-house in vitro potency values generated in different cell-based assays. Additionally, we investigated the correlation with target coverage, expressed as a ratio between the steady state drug exposure and unbound potency, body weight, or HbA1c reduction in patients with T2D. Results: We found that the best correlation with in vivo efficacy was seen for in vitro potency data generated in cellular assays performed in the absence of any serum albumin or using ovalbumin. Residual variability was larger using in vitro potency data generated in endogenous cell lines or in the presence of human serum albumin. For the human receptor assay with no albumin, exposures above 100-fold in vitro EC50 resulted in >1.5% point HbA1c reduction, while a 5% BW reduction was related to approximately 3× higher exposures. A similar relationship was seen in the ovalbumin assay. Conclusions: Overall, the relationship established for in vitro potency and in vivo efficacy will help to increase confidence in human dose prediction and trial design for new GLP-1RAs in the discovery and early clinical phases.

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来源期刊
Pharmaceutics
Pharmaceutics Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
7.90
自引率
11.10%
发文量
2379
审稿时长
16.41 days
期刊介绍: Pharmaceutics (ISSN 1999-4923) is an open access journal which provides an advanced forum for the science and technology of pharmaceutics and biopharmaceutics. It publishes reviews, regular research papers, communications,  and short notes. Covered topics include pharmacokinetics, toxicokinetics, pharmacodynamics, pharmacogenetics and pharmacogenomics, and pharmaceutical formulation. Our aim is to encourage scientists to publish their experimental and theoretical details in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.
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