Department of Pharmacy and Pharmaceutical Technology School of Pharmacy, University of Navarra, Pamplona, 31080, Navarra, Spain.
Pharm Res. 2012 Jun;29(6):1518-29. doi: 10.1007/s11095-011-0648-6. Epub 2012 Jan 5.
Flibanserin is being developed for treating hypoactive sexual desire disorder in women; the main side effect is sedation. The analysis objective was to relate flibanserin plasma concentrations with acute sedative effects using a population pharmacokinetic/pharmacodynamic (PK/PD) model.
The population model was developed with NONMEM based on data from 24 healthy volunteers. "Drowsiness" was serially assessed by a Visual Analogue Scale (VAS) on a baseline day and after morning oral administration of 100 mg flibanserin together with PK sampling.
PK was best described by a three-compartment disposition model and transit compartments accounting for the lag time in absorption. VAS "drowsiness" baseline profiles were modeled using linear splines with three breakpoints located at clock times at first and last observation, and at the median of the observation time across subjects. The drug effect followed a sigmoidal E(MAX) model using predicted effect site concentrations (C(e)). The VAS vs. C(e) relationship was very steep and effect site and plasma concentration-time profiles were very similar thus suggesting little delay between the occurrence of maximum flibanserin plasma concentrations and drowsiness.
At effect site concentrations lower than ≈ 200 ng/mL that are reached approximately 4 h after administration, flibanserin shows hardly any effect on the VAS "drowsiness" scale.
氟班色林正在开发用于治疗女性性欲低下障碍；主要副作用是镇静。分析目的是使用群体药代动力学/药效学（PK/PD）模型将氟班色林的血浆浓度与急性镇静作用相关联。
基于 24 名健康志愿者的 PK 数据，采用 NONMEM 开发了群体模型。“困倦”通过视觉模拟量表（VAS）在基线日和早晨口服 100mg 氟班色林后进行连续评估，同时进行 PK 采样。
PK 最好通过三房室分布模型和转运室来描述，转运室解释了吸收的滞后时间。VAS“困倦”基线谱采用线性样条进行建模，三个断点位于首次和最后观察的时钟时间，以及在受试者的观察时间中位数处。药物效应采用预测效应部位浓度（C(e)）的 sigmoidal E(MAX)模型进行描述。VAS 与 C(e)的关系非常陡峭，效应部位和血浆浓度-时间曲线非常相似，因此表明在达到最大氟班色林血浆浓度和困倦之间几乎没有延迟。
在给药后约 4 小时达到的低于约 200ng/mL 的效应部位浓度下，氟班色林对 VAS“困倦”量表几乎没有影响。
