de Velde Femke, de Winter Brenda C M, Koch Birgit C P, van Gelder Teun, Mouton Johan W
Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands
Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands.
J Antimicrob Chemother. 2016 Oct;71(10):2909-17. doi: 10.1093/jac/dkw226. Epub 2016 Jun 20.
To describe the population pharmacokinetics of oral amoxicillin and to compare the PTA of current dosing regimens.
Two groups, each with 14 healthy male volunteers, received oral amoxicillin/clavulanic acid tablets on two separate days 1 week apart. One group received 875/125 mg twice daily and 500/125 mg three times daily and the other group 500/125 mg twice daily and 250/125 mg three times daily. A total of 1428 amoxicillin blood samples were collected before and after administration. We analysed the concentration-time profiles using a non-compartmental pharmacokinetic method (PKSolver) and a population pharmacokinetic method (NONMEM). The PTA was computed using Monte Carlo simulations for several dosing regimens.
AUC0-24 and Cmax increased non-linearly with dose. The final model included the following components: Savic's transit compartment model, Michaelis-Menten absorption, two distribution compartments and first-order elimination. The mean central volume of distribution was 27.7 L and mean clearance was 21.3 L/h. We included variability for the central volume of distribution (34.4%), clearance (25.8%), transit compartment model parameters and Michaelis-Menten absorption parameters. For 40% fT>MIC and >97.5% PTA, the breakpoints were 0.125 mg/L (500 mg twice daily), 0.25 mg/L (250 mg three times daily and 875 mg twice daily), 0.5 mg/L (500 mg three times daily) and 1 mg/L (750, 875 or 1000 mg three times daily and 500 mg four times daily).
The amoxicillin absorption rate appears to be saturable. The PTAs of high-dose as well as twice-daily regimens are less favourable than regimens with lower doses and higher frequency.
描述口服阿莫西林的群体药代动力学，并比较当前给药方案的目标达成概率（PTA）。
两组，每组14名健康男性志愿者，在相隔1周的两天分别口服阿莫西林/克拉维酸片。一组每日两次服用875/125mg，每日三次服用500/125mg；另一组每日两次服用500/125mg，每日三次服用250/125mg。给药前后共采集1428份阿莫西林血样。我们使用非房室药代动力学方法（PKSolver）和群体药代动力学方法（NONMEM）分析浓度-时间曲线。使用蒙特卡洛模拟计算几种给药方案的PTA。
AUC0-24和Cmax随剂量呈非线性增加。最终模型包括以下成分：萨维奇转运室模型、米氏吸收、两个分布室和一级消除。平均中央分布容积为27.7L，平均清除率为21.3L/h。我们纳入了中央分布容积（34.4%）、清除率（25.8%）、转运室模型参数和米氏吸收参数的变异性。对于40% fT>MIC和>97.5% PTA，断点分别为0.125mg/L（每日两次500mg）、0.25mg/L（每日三次250mg和每日两次875mg）、0.5mg/L（每日三次500mg）和1mg/L（每日三次750、875或1000mg以及每日四次500mg）。
阿莫西林的吸收速率似乎是可饱和的。高剂量以及每日两次给药方案的PTA不如低剂量和高频率给药方案。
