Hopkins Ashley M, Wojciechowski Jessica, Abuhelwa Ahmad Y, Mudge Stuart, Upton Richard N, Foster David J R
Australian Centre for Pharmacometrics and Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia
Australian Centre for Pharmacometrics and Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
Antimicrob Agents Chemother. 2017 Feb 23;61(3). doi: 10.1128/AAC.02401-16. Print 2017 Mar.
The literature presently lacks a population pharmacokinetic analysis of doxycycline. This study aimed to develop a population pharmacokinetic model of doxycycline plasma concentrations that could be used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC. Doxycycline pharmacokinetic data were available from eight phase 1 clinical trials following single/multiple doses of conventional-release doxycycline capsules, Doryx delayed-release tablets, and Doryx MPC under fed and fasted conditions. A population pharmacokinetic model was developed in a stepwise manner using NONMEM, version 7.3. The final covariate model was developed according to a forward inclusion ( < 0.01) and then backward deletion ( < 0.001) procedure. The final model was a two-compartment model with two-transit absorption compartments. Structural covariates in the base model included formulation effects on relative bioavailability (), absorption lag (ALAG), and the transit absorption rate (KTR) under the fed status. An absorption delay (lag) for the fed status (FTLAG2 = 0.203 h) was also included in the model as a structural covariate. The fed status was observed to decrease by 10.5%, and the effect of female sex was a 14.4% increase in clearance. The manuscript presents the first population pharmacokinetic model of doxycycline plasma concentrations following oral doxycycline administration. The model was used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC, and it could potentially be used to critically examine and optimize doxycycline dose regimens.
目前的文献中缺乏对多西环素的群体药代动力学分析。本研究旨在建立一个多西环素血浆浓度的群体药代动力学模型，该模型可用于评估多西环素缓释片（Doryx）和多西环素MPC之间的生物等效性效力。多西环素的药代动力学数据来自八项1期临床试验，这些试验在进食和空腹条件下，单次/多次给予常规释放的多西环素胶囊、多西环素缓释片（Doryx）和多西环素MPC。使用NONMEM 7.3版逐步建立群体药代动力学模型。最终的协变量模型是根据向前纳入（<0.01）然后向后剔除（<0.001）程序建立的。最终模型是一个具有两个转运吸收室的二室模型。基础模型中的结构协变量包括制剂对进食状态下相对生物利用度（）、吸收延迟（ALAG）和转运吸收率（KTR）的影响。模型中还包括进食状态下的吸收延迟（滞后）（FTLAG2 = 0.203小时）作为结构协变量。观察到进食状态使 降低10.5%，女性的影响是清除率增加14.4%。本文首次提出了口服多西环素后多西环素血浆浓度的群体药代动力学模型。该模型用于评估多西环素缓释片（Doryx）和多西环素MPC之间的生物等效性效力，并且有可能用于严格审查和优化多西环素的给药方案。
