Andresen V, Camilleri M
Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Neurogastroenterol Motil. 2006 May;18(5):354-60. doi: 10.1111/j.1365-2982.2006.00779.x.
There is a need to have predictive biomarkers to test novel experimental medicines in functional gastrointestinal disorders. The human pharmacodynamic models and biomarkers pertaining to two important conditions are reviewed in a two-part article: functional dyspepsia (part I) and visceral pain (part II). With visceral pain models, the large coefficient of variation in sensation end points in human studies precludes definitive conclusions such as go/no go decisions or dose selection for phase IIb or III studies, unless very large numbers of patients are evaluated in phase IIA pharmacodynamic studies. This renders such pharmacological studies ambitious, or unachievable in a timely fashion. Moreover, the results of tests and clinical trials should be interpreted with greater knowledge of the drug pharmacokinetics, including the influence of CYP metabolism and potential drug interactions. Thus, it is important to identify valid biomarkers of visceral pain for the assessment of treatment response in pharmacodynamic studies. In this second part of a two-part article, we shall discuss the special challenges in developing medications for visceral pain and the general importance of including pharmacokinetic and pharmacogenomic studies in drug development programmes.
在功能性胃肠疾病中，需要有预测性生物标志物来测试新型实验药物。在一篇分两部分的文章中，对与两种重要病症相关的人体药效学模型和生物标志物进行了综述：功能性消化不良（第一部分）和内脏痛（第二部分）。在内脏痛模型中，人体研究中感觉终点的变异系数很大，这使得无法得出明确的结论，如是否进入下阶段研究的决定或IIb期或III期研究的剂量选择，除非在IIA期药效学研究中评估大量患者。这使得此类药理学研究雄心勃勃，或者无法及时实现。此外，测试和临床试验的结果应结合对药物药代动力学的更多了解来解释，包括CYP代谢的影响和潜在的药物相互作用。因此，识别有效的内脏痛生物标志物对于药效学研究中治疗反应的评估很重要。在这篇分两部分文章的第二部分中，我们将讨论开发内脏痛药物的特殊挑战以及在药物开发计划中纳入药代动力学和药物基因组学研究的普遍重要性。
