Rowland Angela, Mangoni Arduino A, Hopkins Ashley, Sorich Michael J, Rowland Andrew
Department of Clinical Pharmacology, School of Medicine, Flinders University Adelaide, SA, Australia.
Department of Clinical Pharmacology, School of Medicine, Flinders UniversityAdelaide, SA, Australia; Precision Medicine Group, Flinders Center for Innovation in Cancer, School of Medicine, Flinders University AdelaideSA, Australia.
Front Pharmacol. 2016 Dec 27;7:517. doi: 10.3389/fphar.2016.00517. eCollection 2016.
cocktail pathway phenotyping (ICPP) is routinely used to assess the metabolic drug-drug interaction (mDDI) potential of new drug candidates (NDC) during drug development. However, there are a number of potential limitations to this approach and the use of validated drug cocktails and study protocols is essential. Typically ICPP mDDI studies assess only the impact of interactions following multiple postulated perpetrator doses and hence the emphasis in terms of validation of these studies has been ensuring that there are no interactions between probe substrates. Studies assessing the comparative impact of single and multiple doses of the postulated perpetrator have the potential to provide richer information regarding both the clinical impact and mechanism of mDDIs. Using modafinil as a model compound, we sought to develop an optimized ICPP mDDI study protocol to evaluate the potential magnitude and clinical relevance of mDDIs using a physiologically based pharmacokinetic modeling approach.
鸡尾酒途径表型分析（ICPP）在药物开发过程中通常用于评估新候选药物（NDC）的代谢性药物-药物相互作用（mDDI）潜力。然而，这种方法存在一些潜在局限性，使用经过验证的药物鸡尾酒和研究方案至关重要。通常，ICPP mDDI研究仅评估多个假定肇事者剂量后相互作用的影响，因此这些研究验证的重点一直是确保探针底物之间不存在相互作用。评估单剂量和多剂量假定肇事者的比较影响的研究有可能提供有关mDDIs临床影响和机制的更丰富信息。我们以莫达非尼作为模型化合物，试图开发一种优化的ICPP mDDI研究方案，使用基于生理的药代动力学建模方法来评估mDDIs的潜在强度和临床相关性。
