Non-linear absorption pharmacokinetics of amoxicillin: consequences for dosing regimens and clinical breakpoints
Non-linear absorption pharmacokinetics of amoxicillin: consequences for dosing regimens and clinical breakpoints
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DOI：
10.1093/jac/dkw226
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发表时间：
2016-10-01
影响因子：
5.2
通讯作者：
Mouton, Johan W.
中科院分区：
文献类型：
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作者：
de Velde, Femke;de Winter, Brenda C. M.;Mouton, Johan W.
为了描述阿莫西林口服的群体药代动力学，比较目前给药方案的PTA。两组健康男性志愿者各14名，分别在一周内的两天口服阿莫西林/克拉维酸片剂。一组口服875/125 mg，每日两次和500/125 mg，每日三次；另一组500/125 mg，每日两次，250/125 mg，每日三次。服药前后共采集阿莫西林血样1428份。我们使用非隔室药代动力学方法(PKSolver)和群体药代动力学方法(NONMEM)分析了药物的浓度-时间分布。用蒙特卡罗模拟计算了几种给药方案的PTA，AUC(0-24)和C-max随剂量的增加呈非线性增加。最终模型包括以下几个部分：Savic转运模型、Michaelis-Menten吸收模型、两个分配室和一级消除。平均中心分布体积为27·7 L，平均清除为21·3 L/h，包括中心分布体积(34·4%)、清除(25·8%)、传输室模型参数和米氏吸收参数的变异。40%FT(>；MIC)和>；97.5%PTA的崩解点分别为0.125 mg/L(每日2次)、0.25 mg/L(每日3次和875 mg)、0.5 mg/L(每日3次)和1 mg/L(每日3次和4次)。阿莫西林吸收速率呈饱和状态。大剂量和每日两次方案的PTA不如低剂量和高频率的方案有利。
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.AUC(0-24) and C-max 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.