Oncology Clinical Pharmacology, Pfizer Inc., San Diego, California, USA.
Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.
AAPS J. 2020 May 19;22(4):73. doi: 10.1208/s12248-020-00455-y.
Sertraline pharmacokinetics is poorly understood and highly variable due to large between-subject variability with inconsistent reports for oral bioavailability. The study objective was to characterize sertraline pharmacokinetics by developing and validating a sertraline population pharmacokinetic (PK) model in healthy subjects using published clinical PK data. We carried a systematic literature search in PubMed in October 2015 and identified 27 pharmacokinetic studies of sertraline conducted in healthy adult subjects and reported in the English language. Sixty mean plasma concentration-time profiles made of 748 plasma concentrations following IV, single, and multiple oral doses ranging from 5 to 400 mg were extracted and analyzed for dose proportionality by a log-linear model and fitted to a 2-compartment pharmacokinetic model in NONMEM using a model-based meta-analysis (MBMA) approach. After a single oral dose, sertraline C and AUC increased with dose proportionally between 50 and 200 mg, and bioavailability increased nonlinearly with dose from 5 to 50 mg and plateaued afterwards while T and t did not change with dose. Following multiple oral doses, C and AUC increased proportionally with dose across the entire dose range (5-200 mg) while bioavailability, T, and t remained constant with dose. Sertraline absorption was time-dependent and best described by a sigmoidal E function of time after dose. Study findings indicate that sertraline PK is linear in healthy adult subjects at doses ≥ 50 mg, and exposures were nonlinear only after single oral doses < 50 mg likely due to reduced bioavailability.
舍曲林的药代动力学特性了解甚少且变异性较大，这主要是由于个体间的变异性很大，口服生物利用度的报告也不一致。本研究旨在通过对健康受试者的舍曲林临床药代动力学（PK）数据进行开发和验证，建立舍曲林群体 PK 模型来阐明其 PK 特征。我们于 2015 年 10 月在 PubMed 上进行了系统的文献检索，共检索到 27 项关于健康成年受试者的舍曲林 PK 研究，这些研究均以英文发表。从 748 个静脉、单次和多次口服（剂量范围为 5-400mg）后获得的 60 个平均血浆浓度-时间曲线中提取数据，并采用对数线性模型分析剂量比例关系，使用基于模型的荟萃分析（MBMA）方法，将数据拟合到 NONMEM 中的 2 室 PK 模型中。单次口服给药后，舍曲林 C 和 AUC 与剂量呈比例增加，在 50-200mg 之间，生物利用度随着剂量从 5-50mg 非线性增加，之后达到平台，而 T 和 t 与剂量无关。多次口服给药后，C 和 AUC 与整个剂量范围（5-200mg）呈比例增加，而生物利用度、T 和 t 与剂量保持不变。舍曲林的吸收呈时间依赖性，且最佳描述为剂量后时间的 S 型 E 函数。研究结果表明，健康成年人的舍曲林 PK 在剂量≥50mg 时呈线性，而单次口服剂量<50mg 时的暴露量是非线性的，这可能是由于生物利用度降低所致。
