一种用于在临床前安全性研究期间评估GLP-1激动肽活性药物水平的体外效力测定法。
An ex vivo potency assay to assess active drug levels of a GLP-1 agonistic peptide during preclinical safety studies.
作者信息
Schäfer Martin, Challand Steven, Schick Eginhard, Bader Sabine, Hainzl Dominik, Heinig Katja, Müller Lutz, Papadimitriou Apollon, Heinrich Julia
机构信息
Roche Pharmaceutical Research & Early Development, Pharmaceutical Sciences, Roche Innovation Center Penzberg, Roche Diagnostics GmbH, Nonnenwald 2, 82377 Penzberg, Germany.
Roche Pharmaceutical Research & Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
出版信息
Bioanalysis. 2015 Dec;7(24):3063-72. doi: 10.4155/bio.15.189. Epub 2015 Oct 6.
BACKGROUND
During development of biologics, safety and efficacy assessments are often hampered by immune responses to the treatment. To assess active exposure of a drug peptide in a toxicology study, we developed an ex vivo potency assay which complemented the total drug quantification assay.
METHODOLOGY
Compound activity was assessed in samples of treated monkeys by cell-based cAMP measurements. For each animal, activity was compared with its predose sample to which the compound has been added at the postdose concentration as determined by a total LC-MS/MS assay.
CONCLUSION
We were able to show that despite a high total test compound level, activity was reduced tremendously in antidrug-antibody-positive monkeys. Therefore, the applied ex vivo potency assay supplements drug quantification methods to determine active exposures.
背景
在生物制品的研发过程中，对治疗的免疫反应常常会妨碍安全性和有效性评估。为了在毒理学研究中评估药物肽的活性暴露，我们开发了一种体外效价测定法，作为总药物定量测定法的补充。
方法
通过基于细胞的环磷酸腺苷（cAMP）测量来评估经治疗猴子样本中的化合物活性。对于每只动物，将其活性与其给药前样本进行比较，给药前样本中已添加了通过总液相色谱-串联质谱（LC-MS/MS）测定法确定的给药后浓度的化合物。
结论
我们能够证明，尽管总测试化合物水平很高，但在抗药物抗体阳性的猴子中，活性大幅降低。因此，所应用的体外效价测定法补充了药物定量方法，以确定活性暴露情况。
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