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Purpose <p>Rivaroxaban, a new direct oral anticoagulant (DOAC), has demonstrated better efficacy and safety than traditional anticoagulants. Individualized anticoagulation is crucial in patients with a transjugular intrahepatic portosystemic shunt (TIPS) and portal vein hypercoagulability to avoid stent thrombosis. As TIPS shunts portal blood directly into the systemic circulation and may substantially affect the first-pass extraction/distribution of direct oral anticoagulants, no population prospective pharmacokinetic studies have been published in patients undergoing TIPS placement so far. The goal of this study was to establish a PopPK model for rivaroxaban in post-TIPS patients, investigate clinical covariate effects on PK, and provide an optimized dosing regimen.</p> Methods <p>In this single-centre prospective study, 39 adult patients underwent TIPS and received rivaroxaban 5 or 10&#xa0;mg once daily thereafter. Population PK analysis was conducted in NONMEM with 131 plasma concentrations available from 38 evaluable patients (median age: 56 years; median body weight: 63.8&#xa0;kg). Parameterized model was then applied to simulate steady-state exposure of 5, 7.5, 10, and 15&#xa0;mg once daily regimen.</p> Results <p>The final PopPK model was based on a one-compartment with sequential zero-order followed by first-order absorption kinetics, and included the effects of an absorption lag time and linear elimination. The apparent clearance and volume of distribution were 7.48&#xa0;L/h and 4.75&#xa0;L, respectively. Based on patient-specific simulations of 38 subjects, at the 5&#xa0;mg/day dose, an exposure within predefined limits was potentially preserved in 96.7% of the cases vs. 62.5% for the 10&#xa0;mg/day (thresholds: AUC<sub>ss,24</sub> ≤ 1.77&#xa0;mg·h/L and C<sub>max, ss</sub> ≤ 140&#xa0;µg/L). This trend was confirmed by Monte-Carlo simulations in 1,000 virtual patients and suggests TDM when the higher dosage is given.</p> Conclusions <p>This PopPK model provides an initial characterisation of rivaroxaban disposition in post-TIPS patients and reveals a markedly reduced apparent V/F relative to non-TIPS populations. The 5&#xa0;mg once-daily regimen is generally safe, while the 10&#xa0;mg dose may be considered with therapeutic drug monitoring to account for substantial inter-individual pharmacokinetic variability in post-TIPS patients.</p> Trial registration <p>Chinese Clinical Trial Registry, ChiCTR (ChiCTR2300073784); registered 20 July 2023.</p>

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Population pharmacokinetics of rivaroxaban after transjugular intrahepatic portosystemic shunt

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月24日

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  • Min Jia,
  • Yiming Chai,
  • Yuan Gao,
  • Changyou Jing,
  • Kunlei Zhu,
  • Tong Zhu,
  • Liang Wang,
  • Aili Sun,
  • Jun Yang,
  • Yanqiu Zhu,
  • Yingmei Feng,
  • Yu Cao,
  • Jianjun Li

摘要

Purpose

Rivaroxaban, a new direct oral anticoagulant (DOAC), has demonstrated better efficacy and safety than traditional anticoagulants. Individualized anticoagulation is crucial in patients with a transjugular intrahepatic portosystemic shunt (TIPS) and portal vein hypercoagulability to avoid stent thrombosis. As TIPS shunts portal blood directly into the systemic circulation and may substantially affect the first-pass extraction/distribution of direct oral anticoagulants, no population prospective pharmacokinetic studies have been published in patients undergoing TIPS placement so far. The goal of this study was to establish a PopPK model for rivaroxaban in post-TIPS patients, investigate clinical covariate effects on PK, and provide an optimized dosing regimen.

Methods

In this single-centre prospective study, 39 adult patients underwent TIPS and received rivaroxaban 5 or 10 mg once daily thereafter. Population PK analysis was conducted in NONMEM with 131 plasma concentrations available from 38 evaluable patients (median age: 56 years; median body weight: 63.8 kg). Parameterized model was then applied to simulate steady-state exposure of 5, 7.5, 10, and 15 mg once daily regimen.

Results

The final PopPK model was based on a one-compartment with sequential zero-order followed by first-order absorption kinetics, and included the effects of an absorption lag time and linear elimination. The apparent clearance and volume of distribution were 7.48 L/h and 4.75 L, respectively. Based on patient-specific simulations of 38 subjects, at the 5 mg/day dose, an exposure within predefined limits was potentially preserved in 96.7% of the cases vs. 62.5% for the 10 mg/day (thresholds: AUCss,24 ≤ 1.77 mg·h/L and Cmax, ss ≤ 140 µg/L). This trend was confirmed by Monte-Carlo simulations in 1,000 virtual patients and suggests TDM when the higher dosage is given.

Conclusions

This PopPK model provides an initial characterisation of rivaroxaban disposition in post-TIPS patients and reveals a markedly reduced apparent V/F relative to non-TIPS populations. The 5 mg once-daily regimen is generally safe, while the 10 mg dose may be considered with therapeutic drug monitoring to account for substantial inter-individual pharmacokinetic variability in post-TIPS patients.

Trial registration

Chinese Clinical Trial Registry, ChiCTR (ChiCTR2300073784); registered 20 July 2023.