Yang Jiansong, Kjellsson Maria, Rostami-Hodjegan Amin, Tucker Geoffrey T
Academic Unit of Molecular Pharmacology & Pharmacogenetics, Division of Clinical Sciences (South), University of Sheffield, Sheffield, UK.
Eur J Pharm Sci. 2003 Oct;20(2):223-32. doi: 10.1016/s0928-0987(03)00200-8.
To investigate the effect of dose staggering on metabolic drug-drug interactions (MDDI).
Using Matlab, anatomical, physiological and biochemical data relating to human pharmacokinetics were integrated to create a representative virtual healthy subject relevant to in vivo studies. The effects of dose staggering on AUC and C(max) were investigated under various scenarios with respect to pharmacokinetic characteristics of the inhibitor and substrate drugs (e.g. hepatic extraction ratio). Specific cases were also simulated where MDDI had been studied experimentally for combinations of drugs (budesonide and ketoconazole; triazolam and itraconazole).
The decrease in the magnitude of the inhibitory effect of the 'perpetrator' drug (inhibitor) on the 'victim' drug (substrate) as a result of 'dose staggering' was greater when the 'perpetrator' was given after the 'victim'. There was reasonable agreement between the predicted extent of the interactions and the observed in vivo data (mean prediction errors of 25 and -14% for AUC and C(max) values, respectively (n=7)). The impact of dose staggering was minimal during continuous dosage of inhibitors with long elimination half-lives (e.g. itraconazole, >20 h).
Clinical trial simulations using physiological information may provide useful guidelines for optimal dose staggering when poly-pharmacy is inevitable.
研究剂量错开对代谢性药物相互作用（MDDI）的影响。
使用Matlab，整合与人体药代动力学相关的解剖学、生理学和生化数据，以创建一个与体内研究相关的代表性虚拟健康受试者。在各种情况下，针对抑制剂和底物药物的药代动力学特征（例如肝提取率），研究剂量错开对AUC和C(max)的影响。还模拟了药物组合（布地奈德和酮康唑；三唑仑和伊曲康唑）已进行实验性MDDI研究的特定案例。
当“肇事”药物（抑制剂）在“受害”药物（底物）之后给药时，由于“剂量错开”导致“肇事”药物对“受害”药物的抑制作用强度降低的幅度更大。预测的相互作用程度与观察到的体内数据之间存在合理的一致性（AUC和C(max)值的平均预测误差分别为25%和-14%（n = 7））。在连续给予消除半衰期长的抑制剂（例如伊曲康唑，>20小时）期间，剂量错开的影响最小。
当不可避免地使用多种药物时，使用生理信息进行临床试验模拟可为最佳剂量错开提供有用的指导。
