Astellas Pharma Inc, Tokyo, Japan.
Astellas Pharma Inc, Tokyo, Japan.
Clin Ther. 2020 Jun;42(6):1067-1076.e2. doi: 10.1016/j.clinthera.2020.04.006. Epub 2020 Jun 6.
The objectives of this study were to explore covariates of plasma quetiapine concentrations after oral administration of quetiapine extended-release formulation (XR), and to examine the exposure-response relationship in Japanese patients with bipolar depression, using population pharmacokinetics (PopPK) modeling.
In a multicenter, randomized, double-blind, placebo-controlled study of quetiapine XR in patients with bipolar depression, plasma for the measurement of quetiapine concentration was collected at weeks 2, 4, 8, 12, 20, 28, and 52 during oral administration of 150 or 300 mg once daily of quetiapine XR before bedtime. A PopPK model of quetiapine XR was developed using nonlinear mixed-effects modeling with first-order conditional estimation with interactions. The exposure-response relationship was examined using post-hoc exposures. The post-hoc AUC estimate was plotted against the change in the Montgomery-Åsberg Depression Rating Scale (ΔMADRS) total score from baseline to 8 weeks following once-daily doses at 300 mg.
The final PopPK analysis dataset contained 322 patients and 1162 observations (cutoff data at week 28; cutoff date, February 2016). The plasma quetiapine concentration-time profile in patients with bipolar depression after oral administration of quetiapine XR was represented well using a 1-compartment with first-order absorption model. Covariate analysis led to the selection of γ-glutamyl transpeptidase on apparent oral clearance and body weight on apparent volume of distribution as covariates. The final population mean values of apparent oral clearance and apparent volume of distribution were 87.7 L/h and 277 L, respectively, and the interindividual %CVs were 32.6% and 75.0%, respectively.
The effects of covariates on PK parameters were not large compared with the interindividual variability. In addition, there was no clear relationship between the AUC and ΔMADRS. ClinicalTrials.gov identifier: NCT01725308.
本研究旨在探讨口服喹硫平缓释制剂（XR）后患者血浆中喹硫平浓度的影响因素，并利用群体药代动力学（PopPK）模型研究日本双相抑郁患者的暴露-反应关系。
在一项多中心、随机、双盲、安慰剂对照的喹硫平 XR 治疗双相抑郁患者的研究中，于睡前口服喹硫平 XR150 或 300mg，每日 1 次，在给药后第 2、4、8、12、20、28 和 52 周采集血浆，以测定喹硫平浓度。采用非线性混合效应模型进行群体 PK 分析，采用一阶条件估算法进行模型拟合，模型中包含协变量间的相互作用。利用事后分析暴露量来评估暴露-反应关系。根据 300mg 每日 1 次剂量给药后 8 周时的蒙哥马利-阿斯伯格抑郁评定量表（MADRS）总分的变化（ΔMADRS），将事后 AUC 估计值与 AUC 进行绘图。
最终 PopPK 分析数据集包含 322 例患者和 1162 个观测值（截止日期为第 28 周；截止日期为 2016 年 2 月）。口服喹硫平 XR 后双相抑郁患者的血浆喹硫平浓度-时间曲线可通过 1 室模型加首过吸收模型较好地拟合。协变量分析选择γ-谷氨酰转肽酶（GGT）作为表观清除率的协变量，体质量作为表观分布容积的协变量。群体平均的表观清除率和表观分布容积分别为 87.7L/h 和 277L，个体内变异分别为 32.6%和 75.0%。
与个体间变异性相比，这些协变量对 PK 参数的影响不大。此外，AUC 与 MADRS 变化之间无明确关系。临床试验注册号：NCT01725308。
