Li Zi-Ran, Shen Cong-Huan, Li Rui-Dong, Wang Bei, Li Juan, Niu Wan-Jie, Zhang Li-Jun, Zhong Ming-Kang, Wang Zheng-Xin, Qiu Xiao-Yan
Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai 200040, China.
Department of General Surgery and Liver Transplant Center, Huashan Hospital, Fudan University, Shanghai 200040, China; Institute of Organ Transplant, Fudan University, Shanghai 200040, China.
Eur J Pharm Sci. 2023 May 1;184:106405. doi: 10.1016/j.ejps.2023.106405. Epub 2023 Feb 10.
The magnitude of drug-drug interaction between tacrolimus and voriconazole is highly variable, and individually tailoring the tacrolimus dose when concomitantly administered with voriconazole remains difficult. This study aimed to develop a semiphysiologically based population pharmacokinetic (semi-PBPK) model and a web-based dashboard to identify the dynamic inhibition of tacrolimus metabolism caused by voriconazole and provide individual tacrolimus regimens for Chinese adult liver transplant recipients. A total of 264 tacrolimus concentrations and 146 voriconazole concentrations were prospectively collected from 32 transplant recipients. A semi-PBPK model with physiological compartments including the gut wall, portal vein, and liver was developed using the nonlinear mixed-effects modeling software NONMEM (version 7.4). A web-based dashboard was established in R software (version 3.6.1) to recommend the individual tacrolimus regimens when concomitantly administered with voriconazole. The reversible inhibition of tacrolimus metabolism caused by voriconazole was investigated in both the liver and the gut wall. Moreover, voriconazole could highly inhibit the CYP3A activity in the gut wall more than in the liver. BMI and postoperative days were identified as significant covariates on intrinsic intestinal and hepatic clearance of tacrolimus, respectively. Age and postoperative days were identified as significant covariates on the volume of distribution of voriconazole. The individual tacrolimus regimens when concomitantly administered with voriconazole could be recommended in the dashboard (https://tac-vor-ddi.shinyapps.io/shinyapp3/). In conclusion, the semi-PBPK model successfully described the dynamic inhibition process between tacrolimus and voriconazole, and the web-based dashboard could provide individual tacrolimus regimens when concomitantly administered with voriconazole.
他克莫司与伏立康唑之间的药物相互作用程度高度可变，在与伏立康唑联合使用时单独调整他克莫司剂量仍然困难。本研究旨在建立一个基于半生理学的群体药代动力学（semi-PBPK）模型和一个基于网络的仪表板，以识别伏立康唑对他克莫司代谢的动态抑制作用，并为中国成年肝移植受者提供个性化的他克莫司给药方案。前瞻性地收集了32名移植受者的264个他克莫司浓度和146个伏立康唑浓度。使用非线性混合效应建模软件NONMEM（版本7.4）建立了一个具有包括肠壁、门静脉和肝脏在内的生理隔室的semi-PBPK模型。在R软件（版本3.6.1）中建立了一个基于网络的仪表板，以推荐与伏立康唑联合使用时的个性化他克莫司给药方案。研究了伏立康唑在肝脏和肠壁中对他克莫司代谢的可逆抑制作用。此外，伏立康唑对肠壁中CYP3A活性的抑制作用比对肝脏中的抑制作用更强。BMI和术后天数分别被确定为他克莫司内在肠道清除率和肝脏清除率的显著协变量。年龄和术后天数被确定为伏立康唑分布容积的显著协变量。在仪表板（https://tac-vor-ddi.shinyapps.io/shinyapp3/）中可以推荐与伏立康唑联合使用时的个性化他克莫司给药方案。总之，semi-PBPK模型成功描述了他克莫司与伏立康唑之间的动态抑制过程，基于网络的仪表板可以在与伏立康唑联合使用时提供个性化的他克莫司给药方案。
