Population pharmacokinetics of oxycodone in plasma and cerebrospinal fluid after epidural and intravenous administration

<b>Objectives</b>: To establish the first plasma and cerebrospinal fluid (CSF) oxycodone population pharmacokinetic (PopPK) model after epidural (EPI) and intravenous (IV) oxycodone administration. <b>Methods</b>: The study was conducted with 30 female subjects undergoing elective gynecological surgery with epidural analgesia. A parallel single dose of EPI oxycodone with IV placebo (EPI group; n = 18) or IV oxycodone with EPI placebo (IV group; n = 12) was administered. An epidural catheter for drug administration was placed at T12/L1 and a spinal catheter for CSF sampling at L3/4. Plasma and CSF for oxycodone analysis were frequently collected. A PopPK model was built using the NONMEM software package. <b>Results</b>: Plasma and CSF oxycodone concentrations were evaluated using separate central plasma and CSF compartments and separate peripheral plasma and CSF compartments. Epidural space served as a depot compartment with transfer to both the plasma and CSF central compartments. The population parameters for plasma clearance and apparent distribution volumes for central and peripheral compartments for plasma and CSF were 37.4 L/h, 90.2 L, 68.9 L, 0.035 L (fixed based on literature), and 0.039 L, respectively. <b>Conclusion</b>: A PopPK model was developed and found to precisely and accurately describe oxycodone time-concentration data in plasma and CSF.

研究目标：建立硬膜外（epidural, EPI）与静脉（intravenous, IV）给予羟考酮后，血浆与脑脊液（cerebrospinal fluid, CSF）中羟考酮的群体药代动力学（population pharmacokinetic, PopPK）模型，为该类给药方式下的首个相关模型。

研究方法：本研究纳入30例接受择期妇科手术且行硬膜外镇痛的女性受试者。采用平行分组给药方案，分别给予单剂量硬膜外羟考酮联合静脉安慰剂（硬膜外组，n=18）或静脉羟考酮联合硬膜外安慰剂（静脉组，n=12）。于T12/L1节段置入硬膜外给药导管，于L3/4节段置入用于脑脊液采样的脊髓导管。频繁采集血浆与脑脊液样本以用于羟考酮的浓度分析。采用NONMEM软件构建群体药代动力学模型。

研究结果：本研究分别设置血浆中央室、脑脊液中央室及其各自的外周室，对血浆与脑脊液中的羟考酮浓度进行评估。硬膜外间隙作为药物储库室，可将药物转运至血浆中央室与脑脊液中央室。血浆相关群体药代动力学参数包括：清除率37.4 L/h、中央室表观分布容积90.2 L、外周室表观分布容积68.9 L；脑脊液相关参数为：中央室表观分布容积0.035 L（基于文献固定）、外周室表观分布容积0.039 L。

研究结论：本研究成功构建群体药代动力学模型，该模型可精准且准确地描述血浆与脑脊液中羟考酮的时间-浓度变化数据。