Department of Psychiatry, Crozer Health, Upland, Pennsylvania, USA.
J Clin Pharmacol. 2022 Oct;62(10):1297-1309. doi: 10.1002/jcph.2071. Epub 2022 Jun 1.
Benzodiazepines induce a series of clinical effects by modulating subtypes of γ-aminobutyric acid type A receptors in the central nervous system. The brain concentration-time profiles of diazepam that correspond to these effects are unknown, but can be estimated with physiologically based pharmacokinetic (PBPK) modeling. In this study, a PBPK model for the 1,4-benzodiazepines diazepam and nordiazepam was developed from plasma concentration-time courses with PK-Sim software to predict brain concentrations. The PBPK model simulations accurately parallel plasma concentrations from both an internal model training data set and an external data set for both intravenous and peroral diazepam administrations. It was determined that the unbound interstitial brain concentration-time profiles correlated with diazepam pharmacodynamic end points. With a 30-mg intravenous diazepam dose, the peak unbound interstitial brain concentration from this model is 160 nM at 2 minutes and 28.9 nM at 120 minutes. Peak potentiation of recombinant γ-aminobutyric acid type A receptors composed of α1β2γ2s, α2β2γ2s, and α5β2γ2s subunit combinations that are involved in diazepam clinical endpoints is 108%, 139%, and 186%, respectively, with this intravenous dose. With 10-mg peroral administrations of diazepam delivered every 24 hours, steady-state peak and trough unbound interstitial brain diazepam concentrations are 22.3 ± 7.5 and 9.3 ± 3.5 nM. Nordiazepam unbound interstitial brain concentration is 36.1 nM at equilibrium with this diazepam dosing schedule. Pharmacodynamic models coupled to the diazepam unbound interstitial brain concentrations from the PBPK analysis account for electroencephalographic drug effect, change in 13- to 30-Hz electroencephalographic activity, amnesia incidence, and sedation score time courses from human subjects.
苯二氮䓬类药物通过调节中枢神经系统中γ-氨基丁酸 A 型受体的亚型产生一系列临床效应。对应于这些效应的地西泮的脑浓度-时间曲线尚不清楚，但可以使用基于生理学的药代动力学（PBPK）模型进行估计。在这项研究中，使用 PK-Sim 软件从血浆浓度-时间曲线开发了用于 1,4-苯二氮䓬类药物地西泮和去甲西泮的 PBPK 模型，以预测脑浓度。PBPK 模型模拟与静脉内和口服地西泮给药的内部模型训练数据集和外部数据集的血浆浓度准确平行。确定未结合的细胞外脑浓度-时间曲线与地西泮药效终点相关。在 30mg 静脉内地西泮剂量下，该模型的未结合细胞外脑浓度峰值在 2 分钟时为 160 nM，在 120 分钟时为 28.9 nM。与地西泮临床终点相关的包含 α1β2γ2s、α2β2γ2s 和 α5β2γ2s 亚基组合的重组 γ-氨基丁酸 A 受体的峰值增强分别为 108%、139%和 186%。对于每 24 小时给予 10mg 的口服地西泮剂量，稳态峰和谷未结合细胞外脑地西泮浓度分别为 22.3±7.5 和 9.3±3.5 nM。在此地西泮给药方案下，未结合的去甲西泮细胞外脑浓度达到平衡时为 36.1 nM。与 PBPK 分析中地西泮未结合细胞外脑浓度耦合的药效学模型解释了脑电图药物效应、13-30Hz 脑电图活动变化、遗忘发生率和镇静评分时间过程从人体受试者。
